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Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials
Abstract
Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2‐compartment model with first‐order absorption and lag time for the immediate‐release formulation and mixed zero‐ and first‐order absorption with lag time for the extended‐release formulation, and linear elimination adequately described upadacitinib plasma concentration–time profiles. The oral bioavailability of upadacitinib extended‐release formulation was estimated to be approximately 80% relative to the immediate‐release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady‐state area under the plasma concentration–time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady‐state AUC, while subjects with rheumatoid arthritis had 35% higher steady‐state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady‐state exposures.
... dose range. 14 After administration of the extended-release tables, upadacitinib reaches a maximum plasma concentration (C max ) within 2 to 4 h, followed by a bi-exponential decline with an apparent terminal halflife ranging from 9 to 14 h. Upadacitinib is a substrate for cytochrome P450 (CYP) 3A, and to a minor extent for CYP2D6. ...
... Upadacitinib is a substrate for cytochrome P450 (CYP) 3A, and to a minor extent for CYP2D6. 15 The population pharmacokinetics of upadacitinib in healthy volunteers and those with RA, 16,17 Crohn's disease, ulcerative colitis, and atopic dermatitis, 14 have been described previously. These analyses showed that age, sex, body weight, and race did not have a clinically meaningful effect on upadacitinib plasma exposures and that upadacitinib pharmacokinetics are consistent between these patient populations. ...
... clearance based on population pharmacokinetic analyses, but upadacitinib plasma exposures were estimated to be comparable between patients with mild or moderate renal impairment and those with normal renal function. 14 The work presented here includes the population pharmacokinetics and exposure-response analyses conducted for upadacitinib in patients with axSpA. The objectives of these analyses were to characterize upadacitinib pharmacokinetics in patients with axSpA and to evaluate the relationships between upadacitinib plasma exposures and key efficacy and safety variables. ...
Upadacitinib is an orally administered, selective, Janus kinase inhibitor that is approved for several auto‐immune conditions, such as axial spondyloarthritis, an inflammatory rheumatic disease that includes ankylosing spondylitis (AS) and non‐radiographic axial spondyloarthritis (nr‐axSpA). The approvals of upadacitinib for the treatment of AS and nr‐axSpA were based on the safety and efficacy data for upadacitinib 15 mg once‐daily compared to placebo from the SELECT‐AXIS 1 and SELECT‐AXIS 2 studies. Population pharmacokinetic analyses based on data from 244 patients with axSpA showed that the pharmacokinetics of upadacitinib were comparable in subjects with AS and nr‐axSpA. Exposure‐response relationships were characterized for key efficacy and safety end points using data from 482 patients with axSpA. The exposure‐response analyses for efficacy based on Assessment of SpondyloArthritis International Society (ASAS)20 and ASAS40 responses at week 14, showed a clear differentiation from placebo with no evidence of increased responses with increasing upadacitinib plasma exposures. There were no clear exposure‐response trends observed for safety end points that included serious infections, herpes zoster, pneumonia, lymphopenia (grade ≥3), neutropenia (grade ≥3), or a greater than 2 g/dL decrease in hemoglobin from baseline through week 14. The exposure‐response analyses for efficacy and safety presented here supported the favorable benefit–risk profile with the use of upadacitinib 15 mg once‐daily for the treatment of axSpA.
... A previously published population pharmacokinetic model for upadacitinib in patients with RA, CD, UC, AD, and healthy volunteers (HVs) was used as the basis for this pharmacokinetic analysis. In this previous model, upadacitinib pharmacokinetics were described by a two-compartment model with mixed zero-and first-order absorption with lag time (for the first order absorption) for the upadacitinib QD formulation [14]. Statistically significant covariates identified in the previous model included subject population (HV vs. AD/UC/CD and RA vs. AD/UC/CD), creatinine clearance, and sex, on apparent oral clearance (CL/F), and sex and body weight on apparent volume of distribution of the central compartment (V c /F) were retained in the model for the current analysis. ...
... All model parameters, including covariate effects, from the original model were re-estimated using a combined dataset that included data from Induction phase up to Week 8 of UC Phase 2b/3 studies in addition to the data previously included in the cross-population pharmacokinetic analyses [14]. Different inter-subject variability (ISV) and residual variability model structures were explored in the process of model development by graphical methods to assess model goodness-of-fit (GOF). ...
... Using the previously published population pharmacokinetic model for upadacitinib as a starting point [14], the outlined stepwise covariate selection method was performed. Statistically significant covariates that were included in the model were creatinine clearance, subject population, sex, and aspartate aminotransferase on CL/F; and sex and body weight on V c /F. ...
Background and Objective
Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints.Methods
Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn’s disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5–45 mg once daily (QD) for induction and 15–30 mg QD for maintenance.ResultsUpadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods.Conclusion
These analyses supported selection of upadacitinib UC induction and maintenance doses.Trial RegistrationData from studies NCT02819635 and NCT03653026 were included in these analyses.
... 20 Upadacitinib pharmacokinetics were characterized following the administration of single and multiple doses of the immediate-release and extended-release formulations. [21][22][23][24][25][26] Upadacitinib plasma exposure was approximately dose proportional over the evaluated dose range across clinical studies and displayed no significant accumulation with repeated twice daily dosing using the immediate-release formulation or with once daily dosing using the extended-release formulation. 21,22 The extended-release tablet formulation of upadacitinib was developed to enhance patient compliance and has 76% oral bioavailability relative to the same dose of the immediate-release formulation. ...
... [21][22][23][24][25][26] Upadacitinib plasma exposure was approximately dose proportional over the evaluated dose range across clinical studies and displayed no significant accumulation with repeated twice daily dosing using the immediate-release formulation or with once daily dosing using the extended-release formulation. 21,22 The extended-release tablet formulation of upadacitinib was developed to enhance patient compliance and has 76% oral bioavailability relative to the same dose of the immediate-release formulation. 23 Upadacitinib median time to the maximum observed plasma concentration (C max ) for the extended-release formulation is 2 to 4 hours, and the mean terminalphase elimination half-life is 9 to 14 hours. ...
... Plasma concentrations of upadacitinib were measured using a validated liquid chromatography method with mass spectrometric detection, as previously described. 22,26,33 Upadacitinib pharmacokinetics were characterized using population pharmacokinetics analyses using data from the phase 2b atopic dermatitis study, and data from phase 1 and phase 2 studies in healthy subjects and subjects with RA, Crohn's disease, and ulcerative colitis. Details of the population pharmacokinetic analyses were previously reported. ...
Upadacitinib is a selective Janus kinase 1 inhibitor that was recently approved for treatment of rheumatoid arthritis and is currently being evaluated for treatment of several other autoimmune diseases, including atopic dermatitis (AD). The relationships between upadacitinib plasma exposure and efficacy (assessed as Eczema Area Severity Index [EASI]-75, EASI-90, and Investigator Global Assessment [IGA] 0/1) in subjects with moderate to severe atopic dermatitis were characterized using the data from 167 subjects who were enrolled in a phase 2b dose-ranging study. Subjects were randomized to receive once daily doses of monotherapy treatment with upadacitinib extended-release 7.5, 15, or 30 mg or placebo for 16 weeks. Logistic regression models were developed and utilized to simulate efficacy for upadacitinib with an approximate phase 3 sample size. Based on exposure-response models, 15 mg once daily is predicted to achieve EASI-75, EASI-90, and IGA 0/1 responses in 48%, 26%, and 29% of subjects, respectively, compared with placebo responses of 9%, 2%, and 2%, respectively, whereas 30 mg once daily is predicted to provide an additional approximately 20% greater efficacy for these end points relative to 15 mg once daily. These analyses supported the selection of upadacitinib doses that are being evaluated in ongoing global phase 3 studies in atopic dermatitis.
... Structural covariates known to be highly influential a priori were built into the structural model. For example, allometric scaling on PK parameters using body weight (exponents of 0.75 and 1 for CL and volume parameters, respectively, referenced to 70 kg), effect of inflammatory disease burden on ritlecitinib CL (consistent with observations made with other Janus kinase inhibitors), and dose, formulation, and high-fat meal effects on absorption parameters [9][10][11][12][13]. ...
... Covariate analyses identified several predictors of differences in ritlecitinib exposure. Patients with inflammatory disease (i.e., RA, AA, UC, and vitiligo) have lower baseline [9,11,13,18]. For a drug metabolized by Dose−Normalized Ratio Compared to 50 mg QD at Steady−State multiple CYP and glutathione-S-transferase enzymes, it is realistic to suspect that systemic inflammation is sufficiently high in patients with inflammatory disease to drive downregulation of metabolic pathways. ...
Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor undergoing parallel clinical development for alopecia areata, vitiligo, ulcerative colitis, Crohn’s disease, and rheumatoid arthritis.
As studies read out simultaneously, strategic planning of population pharmacokinetic model development and evaluation is required to ensure timely decisions.
Data from healthy participants and patients from 12 clinical trials between December 2014 and July 2021 were included: seven phase I studies in healthy participants and organ impairment, five phase II/III studies in patients with rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo. Population pharmacokinetic models consisted of stepwise procedures to accommodate data availability and the model’s application to answering clinical development questions. At each iteration of the model update, parameters of the next model were re-estimated by leveraging previous information and new data.
Three model development lifecycle iterations of the ritlecitinib population pharmacokinetic model were conducted to support alopecia areata, vitiligo, and ulcerative colitis study readouts. Initial structural modeling based on healthy participant data (and some rheumatoid arthritis and alopecia areata data) in iteration 1 provided a platform for comprehensive covariate testing during iteration 2, and model evaluation and implementation of the frequentist prior approach in iteration 3. The final model was a two-compartment model with first-order absorption and direct-response non-stationary clearance and bioavailability driven by concentrations in the peripheral compartment.
The present approach demonstrated the evolution of three population pharmacokinetic models with accumulating data, addressed clinical drug development questions related to systemic exposures of ritlecitinib, and informed the approved product label.
NCT02309827, NCT02684760, NCT02958865, NCT02969044, NCT03232905, NCT03732807, NCT04016077, NCT03715829, NCT04037865, NCT04004663, NCT04634565, NCT02974868.
... 2, is summarised in Fig. 4. Knowing there are several modified physiological parameters in the GI tract of CD patients, the number of cases that passed the rigor of the inclusion criteria was not sufficiently high to indicate a consistent trend. For instance, the exposure of CYP3A substrates did not show the same magnitude of change [39,42,43,[50][51][52][53][54][55][56] in the same phase of the disease (active/inactive). Also, when S-and R-verapamil [50] and midazolam and budesonide [39] were given to the same CD patients, the exposure behaviour was not similar. ...
... A literature search for HSA in CD patients and healthy adults identified a total of 27 studies (Fig. 11a). In 26 studies, participants with active and inactive CD had a lower albumin level compared with controls [52,55,57,, where one study used serum sialic acid as the activity indicator [134], which did not show a difference in the albumin changes compared to other studies that used the CDAI and HBI, and one study showed a slightly higher albumin level in inactive CD patients, where all participants had undergone an ileocecal resection [62]. Our analysis showed a statistically significant decrease in HSA in both CD phases, with active CD exhibiting a higher drop relative to healthy volunteers (Fig. 11b). ...
Backgrond and Objective
Crohn’s disease (CD) is a chronic inflammatory bowel disease that affects a wide age range. Hence, CD patients receive a variety of drugs over their life beyond those used for CD itself. The changes to the integrity of the intestine and its drug metabolising enzymes and transporters (DMETs) can alter the oral bioavailability of drugs. However, there are other changes in systems parameters determining the fate of drugs in CD, and understanding these is essential for dose adjustment in patients with CD.Methods
The current analysis gathered all the available clinical data on the kinetics of drugs in CD (by March 2021), focusing on orally administered small molecule drugs. A meta-analysis of the systems parameters affecting oral drug pharmacokinetics was conducted. The systems information gathered on intestine, liver and blood proteins and other physiological parameters was incorporated into a physiologically based pharmacokinetic (PBPK) platform to create a virtual population of CD patients, with a view for guiding dose adjustment in the absence of clinical data in CD.ResultsThere were no uniform trends in the reported changes in reported oral bioavailability. The nature of the drug as well as the formulation affected the direction and magnitude of variation in kinetics in CD patients relative to healthy volunteers. Even for the same drug, the reported changes in exposure varied, possibly due to a lack of distinction between the activity states of CD. The highest alteration was seen with S-verapamil and midazolam, 8.7- and 5.3-fold greater exposure, respectively, in active CD patients relative to healthy volunteers. Only one report was available on liver DMETs in CD, and indicated reduced CYP3A4 activity. In a number of reports, mRNA expression of DMETs in the ileum and colon of CD patients was measured, focussing on P-glycoprotein (p-gp) transporter and CYP3A4 enzyme, and showed contradictory results. No data were available on protein expression in duodenum and jejunum despite their dominant role in oral drug absorption.Conclusion
There are currently inadequate dedicated clinical or quantitative proteomic studies in CD to enable predictive PBPK models with high confidence and adequate verification. The PBPK models for CD with the available systems parameters were able to capture the major physiological influencers and the gaps to be filled by future research. Quantification of DMETs in the intestine and the liver in CD is warranted, alongside well-defined clinical drug disposition studies with a number of index drugs as biomarkers of changes in DMETs in these patients, to avoid large-scale dedicated studies for every drug to determine the effects of disease on the drug’s metabolism and disposition and the consequential safety and therapeutic concerns.
... The selective JAK1/JAK3 inhibitor tofacitinib and the selective JAK1/JAK2 inhibitor baricitinib are effective and are approved by the FDA and EMA for the treatment of RA, especially for those intolerant or unresponsive to DMARDs [19]. Upadacitinib and filgotinib are selective JAK1 inhibitors, and both have shown good results in patients with RA in phase II and III studies [19,181,182]. The JAK1/JAK3 inhibitor, peficitinib, has also been shown to be effective in patients with RA, but the data from phase III trials are still pending [183,184]. ...
... Several inhibitors blocking specific molecules in the type I IFN signaling pathway, such as tofacitinib and baricitinib for the treatment of RA, are licensed by the FDA/EMA, and more are currently undergoing clinical trials [19]. There are encouraging signs that many targeted inhibitors have completed or entered phase III clinical trials and seem to be very promising, including the anti-IFNAR1 mAb anifrolumab for SLE [20,168]; JAK1/JAK2 inhibitor baricitinib for SLE [21]; and the JAK1 inhibitors upadacitinib and filgotinib for RA [181,182]. Tofacitinib has completed a phase III clinical trial in [198]. Other studies are still not completed so results are unavailable. ...
Type I interferons (IFN-Is) are a very important group of cytokines that are produced by innate immune cells but also act on adaptive immune cells. IFN-Is possess antiviral, antitumor, and anti-proliferative effects, as well are associated with the initiation and maintenance of autoimmune disorders. Studies have shown that aberrantly expressed IFN-Is and/or type I IFN-inducible gene signatures in the serum or tissues of patients with autoimmune disorders are linked to their pathogenesis, clinical manifestations, and disease activity. Type I interferonopathies with mutations in genes impacting the type I IFN signaling pathway have shown symptoms and characteristics similar to those of systemic lupus erythematosus (SLE). Furthermore, both interventions in animal models and clinical trials of therapies targeting the type I IFN signaling pathway have shown efficacy in the treatment of autoimmune diseases. Our review aims to summarize the functions and targeted therapies (as well as clinical trials) of IFN-Is in both adult and pediatric autoimmune diseases, such as SLE, pediatric SLE (pSLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), Sjögren syndrome (SjS), and systemic sclerosis (SSc), discussing the potential abnormal regulation of transcription factors and epigenetic modifications and providing a potential mechanism for pathogenesis and therapeutic strategies for future clinical use.
... Upadacitinib pharmacokinetics in patients with SLE were consistent with the previously characterized pharmacokinetics in patients with RA, [35][36][37] supporting the idea that the difference in optimal dose requirement between patients with SLE and RA may be due to the difference in disease characteristics rather than differences in upadacitinib plasma concentrations. Exposureresponse analyses for key efficacy endpoints demonstrated a clear relationship between increasing upadacitinib exposures in patients with SLE and efficacy and supported the greater efficacy benefit for 30 mg QD compared with 15 mg QD. ...
Objective
The 48‐week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV‐599) in adults with moderately to severely active systemic lupus erythematosus (SLE).
Methods
Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV‐599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV‐599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI‐4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group‐Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events.
Results
The study enrolled 341 patients. The ABBV‐599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV‐599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI‐4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV‐599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV‐599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib.
Conclusion
Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV‐599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks.
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... Thus, TOF, BAR, and FIL require dose reduction in patients with impaired kidney function, whereas BAR and FIL are contraindicated in patients with severe kidney dysfunction. Although the renal elimination rate of UPA is less than 20%, it has a 1.3-fold higher AUC inf in patients with moderate renal impairment [15,18]. Therefore, although dose reduction is not required, it is recommended that UPA is cautiously used in patients with severe renal impairment. ...
Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m²): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m²): 551; and CKDb group (eGFR < 45 mL/min/1.73 m²): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m²). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.
... The findings of this systematic review collectively emphasize the potential role of upadacitinib as a novel therapeutic approach for Crohn's disease. Multiple trials have demonstrated substantial improvements in clinical remission rates and endoscopic results, indicating the beneficial effects of this treatment in addressing underlying inflammatory processes and supporting mucosal repair, which are particularly promising for patients with refractory Crohn's disease who do not respond adequately to conventional treatment [20][21][22][23]. ...
Crohn’s disease (CD) presents a formidable challenge as a chronic inflammatory condition. This systematic review aimed to comprehensively assess upadacitinib, a novel Janus kinase (JAK) inhibitor, regarding its efficacy, safety, and mechanistic insights in CD treatment.
A thorough search of electronic databases identified studies investigating upadacitinib's impact on CD patients. Study characteristics, efficacy outcomes (clinical remission and endoscopic response), safety profiles, and mechanistic insights were extracted and qualitatively synthesized.
Methodological quality was assessed using established tools. The synthesis of three studies consistently demonstrated improvements in clinical remission rates and endoscopic outcomes in upadacitinib-treated patients. Adverse events, such as herpes zoster, intestinal perforation, non-melanoma skin cancer, adjudicated cardiovascular events, and anemia, were reported, necessitating vigilant safety monitoring.
Upadacitinib emerges as a promising therapeutic option for CD, supported by its observed clinical benefits and mechanistic implications. However, safety concerns underscore the importance of careful patient selection. These findings contribute to the ongoing discussion surrounding personalized treatment approaches for CD, emphasizing the need for further research to confirm its enduring efficacy and safety.
... The PK models were fit to the data using the first-order conditional estimation method with interaction. A previous population PK model developed using data from HV and participants with AD, RA, Crohn's disease (CD) or ulcerative colitis (UC) was used as the basis for PK model development 31 and was re-fit to the new analysis dataset. This model was a two-compartment model with com- Intersubject variability (ISV) in PK parameters was modelled using a multivariate log-normal distribution (Equation 1): ...
Aims
First, population pharmacokinetic analyses were used to characterize upadacitinib pharmacokinetics in adolescent and adult participants with atopic dermatitis (AD) and to identify patient covariates that may impact upadacitinib pharmacokinetics. Second, the exposure‐response relationship for upadacitinib with efficacy and safety endpoints, and the effect of age and concomitant use of topical corticosteroids (TCS) on the exposure‐response relationship and dose selection for patients with AD were evaluated.
Methods
A two‐compartment model with combined first‐ and zero‐order absorption adequately characterized the upadacitinib concentration‐time profiles in 911 healthy volunteer adolescent and adult participants with AD who received upadacitinib 15 or 30 mg orally once daily (QD) as monotherapy or in combination with TCS for 16 weeks. Logistic regression models were developed to characterize the exposure‐efficacy and safety relationships, and simulations were performed based on final exposure‐response models to predict efficacy responses in participants with AD who received placebo or upadacitinib as monotherapy or in combination with TCS.
Results
Upadacitinib exposures were comparable between adolescents and adults. Mild or moderate renal impairment was predicted to increase the upadacitinib area under the plasma concentration‐time curve from time zero to 24 h after dosing (AUC24) approximately 12% and 25%, respectively, compared to participants with normal renal function. Female participants were predicted to have 20% higher AUC24 compared to male participants. Participants with AD were predicted to have 18% higher AUC24 compared to healthy participants. Simulated clinical efficacy responses showed added clinical efficacy benefit for all endpoints evaluated (8‐14%) with the upadacitinib 30 mg once‐daily regimen compared to 15 mg once‐daily in both age groups. In participants receiving upadacitinib in combination with TCS, significant exposure‐dependent increases in upadacitinib efficacy endpoints were observed. No significant effects of age or weight were identified in any of the exposure‐response models.
Conclusion
The results of these analyses support the dose justification for upadacitinib in adult and adolescent patients with moderate to severe AD.
... For instance, findings in this cohort showed poor correlation in patients with atopic dermatitis with UC in the active phase. This differs greatly from previous studies, 35,36 which marked a correlation between atopic dermatitis as an EIM and UC in the active phase. Similarly, when comparing our results from the PG group, a poor correlation was also shown with UC in the active phase, which also differed from previous reports. ...
There have been previous studies, especially in Western countries and even in some areas in Asia, about extra-intestinal manifestations (EIMs) and its link with the outcome of inflammatory bowel disease (IBD), which includes Crohn's disease (CD), and ulcerative colitis (UC). This link is crucial when discussing a patient's prognosis and important when dealing with UC management. The aim of this study was to clarify the most common comorbidities associated with UC, emphasizing immunologic comorbidities in Japan. This study was a retrospective analysis performed at Nagoya University Hospital. The data collection started in March, 2019, and continued for two years. We retrieved the medical records of 105 patients with UC diagnosis, from which the data of 176 EIMs were extracted and analyzed. Results showed that EIMs with UC in the active phase accounted for 43.7% of total EIMs. Twenty-six patients with immune-mediated inflammatory disease frequently had an active phase (odds ratio [OR] 3.84, 99% CI, 1.44-10.27). Comorbidities showing an active manifestation of symptoms and UC in the active phase were significantly correlated in patients with immunological comorbidities, such as peripheral arthritis (r = 0.97, p < 0.01) and rheumatoid arthritis (RA) (r = 0.99, p < 0.01), as well as in patients with primary sclerosis cholangitis (PSC) (r = 0.98, p < 0.01). In conclusion, this analysis suggests the importance of having full comprehension of how immunological comorbidities affect the natural development of UC, which is of vital importance to prevent further UC complications and properly adjust the management of the disease.
... Upadacitinib (Rinvoq; AbbVie Inc) is being investigated to treat AD in adolescents and adults. [5][6][7][8][9] The week-16 results from the Measure Up 1 and Measure Up 2 studies 10 demonstrated that upadacitinib was superior to placebo across assessments of disease activity, itch, skin pain, and impact of AD on quality of life and had a favorable benefit-risk profile in patients with moderate to severe AD. Clinically and statistically significant improvements in itch were observed as early as 2 days after the first dose of upadacitinib, and skin clearance (≥75% improvement in Eczema Area and Severity Index [EASI]) was observed as early as week 2. 10 Both the 15-mg and 30-mg upadacitinib doses were well tolerated; no new important safety risks beyond the labeled upadacitinib safety profile were observed through week 16. 10 Because AD is a chronic disease, 11,12 the evaluation of the long-term benefit-risk profile of upadacitinib as monotherapy continues in the ongoing blinded extension (BE) period of Measure Up 1 and Measure Up 2. Here, we report results through 52 weeks of the BE period. ...
Importance:
Primary results from the Measure Up 1 and Measure Up 2 studies demonstrated upadacitinib efficacy and safety through 16 weeks in patients with atopic dermatitis. Longer-term outcomes remain unknown.
Objective:
To evaluate long-term (52 weeks) efficacy and safety of upadacitinib treatment in patients with atopic dermatitis.
Design, setting, and participants:
Measure Up 1 and Measure Up 2 are ongoing double-blind, placebo-controlled, replicate phase 3 randomized clinical trials that include adults and adolescents with moderate to severe atopic dermatitis at 151 and 154 centers, respectively. Cutoffs for this analysis were December 21, 2020 (Measure Up 1), and January 15, 2021 (Measure Up 2).
Interventions:
Patients were randomized 1:1:1 to receive once-daily oral upadacitinib 15 mg, 30 mg, or placebo. At week 16, patients randomized at baseline to receive upadacitinib 15 mg (273 and 260 patients in Measure Up 1 and Measure Up 2, respectively) and 30 mg (270 and 268 patients) continued assigned treatment; placebo-treated patients were rerandomized 1:1 to receive upadacitinib 15 mg (121 and 120 patients in Measure Up 1 and Measure Up 2, respectively) or 30 mg (123 and 121 patients) in a double-blinded manner.
Main outcomes and measures:
Safety and efficacy, including 75% improvement in the Eczema Area and Severity Index and Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement, were assessed.
Results:
Measure Up 1 and Measure Up 2 included a total of 1609 patients (mean [SD] age, 33.8 [15.6] years; 727 women [45.2%]; 882 men [54.8%]). Efficacy at week 16 was maintained through week 52. At week 52, 75% improvement in the Eczema Area and Severity Index was achieved by 82.0% (95% CI, 77.0%-86.9%) and 79.1% (95% CI, 73.9%-84.4%) of patients continuing the 15-mg dose and 84.9% (95% CI, 80.3%-89.5%) and 84.3% (95% CI, 79.6%-89.0%) of patients continuing the 30-mg dose (for Measure Up 1 and Measure Up 2, respectively); Validated Investigator Global Assessment for Atopic Dermatitis score of clear (0) or almost clear (1) with 2 or greater grades of improvement was achieved by 59.2% (95% CI, 52.9%-65.5%) and 52.6% (95% CI, 46.2%-59.1%) and 62.5% (95% CI, 56.3%-68.7%) and 65.1% (95% CI, 58.9%-71.2%) of patients in the Measure Up 1 and Measure Up 2 studies, respectively. Treatment discontinuation due to adverse events was low overall but was slightly higher for the upadacitinib 30-mg dose. Both upadacitinib doses were well tolerated with no new safety signals.
Conclusions and relevance:
In this analysis of follow-up data from 2 randomized clinical trials, longer-term treatment of adolescents and adults with moderate to severe atopic dermatitis with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 52 weeks.
Trial registration:
ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2).
... This effect was incorporated on F in the model, suggesting increases in the fraction absorbed by or the fraction bioavailable to patients. It has been suggested that infectious and inflammatory disease states alter activities and expression of drug transporters and drugmetabolizing enzymes, such as CYP [19][20][21][22][23]. For a drug primarily metabolized by CYP, it is realistic to suspect that inflammation is sufficiently high in patients with psoriasis or AD to drive downregulation of intestinal/hepatic metabolism, and the first-pass effect. ...
Background and objective:
Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.
Methods:
Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (Cmax) and area under the curve (AUC) were conducted using the final model.
Results:
A two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in Cmax and AUC, respectively. The overall distribution of exposures (Cmax and AUC) was similar in adolescents and adults after accounting for differences in total body weight.
Conclusions:
A population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful.
Clinical trial numbers:
NCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.
... Although filgotinib and upadacitinib show a promising curative effect for IBD, to our knowledge, no reports have identified the use of these immunosuppressors in the treatment of EIMs. There is no shortage of articles on the use of filgotinib or upadacitinib to treat RA, atomic dermatitis, or other autoimmune diseases [91][92][93], but few have explored the efficacy and safety of those drugs for EIMs. This may be attributed to the previously mentioned situation in which only TOF is currently approved for treatment of UC. ...
Background and aims
Extraintestinal manifestations (EIMs) are commonly seen in patients with inflammatory bowel disease (IBD); management of EIMs is difficult and increases the primary disease burden. Recently, tofacitinib (TOF) was reported to be a promising option for treatment of EIMs. We aimed to review published articles and report experience to date.
Methods
The PubMed, Cochrane Library, and Web of Science databases were searched to identify eligible studies. The inclusion criteria were as follows: confirmed diagnosis of IBD; definitive EIMs; treatment with TOF; human study and published in English. The Newcastle–Ottawa Scale score and Cochrane Collaboration’s tool for assessing risk of bias were used to determine the quality of the selected studies.
Results
Twenty-three studies met the inclusion criteria and were included. For nonrandomized studies, 16 were low quality, 5 were moderate quality, and 1 was high quality. For the one randomized controlled trial, the overall bias risk was low. The most concerning EIMs were dermatological manifestations, rheumatologic manifestations, and others, such as primary sclerosing cholangitis, autoimmune hepatitis, uveitis, and Takayasu arteritis. After administering doses of 5–20 mg/d TOF, the included studies reported varying degrees of clinical remission for both the primary disease and EIMs, except for musculoskeletal EIMs.
Conclusion
TOF might benefit EIMs in IBD, especially ulcerative colitis, and elevated dosages and longer treatment times may increase its effectiveness. Manifestation-specific results and large prospective studies are highly warranted.
... In terms of pharmacokinetics, upadacitinib demonstrates proportional dosing between 1 and 48 mg for immediate release (IR) and 7.5-45 mg for extended-release (ER) forms respectively. The former also showed a 76.2% lower oral bioavailability compared to the latter in a population pharmacokinetic analysis [17][18][19]. The ER formulation will be available for commercial use following its success in the pivotal SELECT-PsA trials that resulted in EU approval [20]. ...
Introduction
Psoriatic arthritis is an extra-cutaneous manifestation affecting up to 40% of psoriasis patients with multiple therapies recommended by international guidelines including conventional and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) as well as biologics. Janus kinase inhibitors (JAKis) have emerged as a unique therapeutic target with tofacitinib the first to gain FDA approval in 2017. The non-selectivity of older JAKis increases the risk of off-target effects such as suppression of hemopoiesis hence the rationale for more selective alternatives.
Areas covered
This paper explores the use of upadacitinib (a selective JAK1 inhibitor) for the treatment of psoriatic arthritis. It covers its chemical properties, pharmacokinetics, pharmacodynamics, efficacy, safety and regulation.
Expert opinion
In our opinion, upadacitinib is set to play an important role in the treatment of psoriatic arthritis as demonstrated by the SELECT-PsA trials especially in patients with poor or non-response to current first-line therapies. It's JAK1 receptor selectivity promises a lower side effect profile compared to the older nonselective JAKis but this will require confirmation with long-term clinical trial data.
... Moreover, it seems questionable whether the dose levels for an optimized anti-inflammatory effect of the individual JAKi are identical to those of an antipruritic effect. In addition, the variability of bioavailability depending on the indication, population, and age should be considered [32][33][34]. Due to the large number of JAKi in development for different indications and the inhomogeneous data situation, only head-to-head studies will be able to prove relevant differences in clinically effective preparations. However, the significance of the data presented is limited by methodological constraints. ...
Background:
Itching is considered to be a subjective symptom of the activation of neurosensory structures by different signal molecules and trigger factors. The signaling cascades responsible for it are closely linked to inflammatory processes. This explains why itching also occurs in many inflammatory diseases. One of these signaling cascades is mediated by Janus kinases (JAKs). Recently, it could be shown on a molecular level that Janus kinase 1 (JAK1) directly activates frontal cortex neurons and thus can cause chronic itching.
Objectives:
This study deals with the influence of different JAK inhibitors (JAKi) on the activity of chip-based neural networks of cultured frontal cortex neurons by investigating neurophysiological activity parameters. This in vitro model provides information on dose-dependent effects of model substances with different specificity regarding the inhibition of different JAKs.
Methods:
Tofacitinib (pan-JAKi), baricitinib (JAK1/2i), and upadacitinib (JAK1i) in a concentration range from 10 nmol/L to 50 μmol/L were tested in a microelectrode array neurochip culture system.
Results:
The results show that the inhibition of the neuronal activity of frontal cortex neurons increases with JAK1 selectivity and is dependent on concentration.
Conclusion:
These observations are supported by data from clinical studies in atopic dermatitis and psoriasis. The clinical relevance of these results must be proven by further clinical studies with subjective and objective parameters for itching.
... [18][19][20][21][22][23][24] Upadacitinib pharmacokinetics were similar across different patient populations, such as RA, ulcerative colitis (UC), Crohn's disease (CD), and atopic dermatitis (AD). 1,[25][26][27] Upadacitinib exposures associated with optimal clinical benefit differed from indication to indication due to the individual pathophysiological nature of each condition. In patients with RA, optimal benefit-risk exposures were achieved by the 15 mg once daily (q.d.) dose using the extended-release formulation. ...
Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase 3 studies which evaluated upadacitinib 15 and 30mg QD. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in PsA patients were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in RA patients. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1,916 PsA patients. The percentage of patients achieving efficacy endpoints at Week 12 (ACR50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, while no clear exposure‐response trend was observed for ACR20 at Week 12 or ACR20/50/70 at Week 24 within the range of plasma exposures evaluated in the phase 3 PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin <8g/dL, lymphopenia (Grade≥3), or neutropenia (Grade≥3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease >2g/dL from baseline at Week 24. Based on exposure‐response analyses, the upadacitinib 15mg QD regimen is predicted to achieve robust efficacy in PsA patients and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.
... [1][2][3][4][5][6] The approved dose of upadacitinib in subjects with moderate to severe RA is 15 mg once daily using an extended-release formulation based on results from phase 3 clinical trials that evaluated both 15 mg and 30 mg once daily doses and demonstrated that upadacitinib 15 mg once daily maximizes efficacy in RA. [4][5][6][7][8][9][10][11] Upadacitinib pharmacokinetics have been characterized in healthy subjects and in patient populations for several autoimmune diseases (eg, RA, Crohn disease, ulcerative colitis). 9,[12][13][14][15][16] Upadacitinib is a nonsensitive substrate of cytochrome P450 (CYP) 3A. 12,17 In a clinical cocktail drug interaction study, administration of upadacitinib 30 mg once daily (twice the approved dose in RA) in healthy subjects resulted in a decrease in midazolam area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (C max ) of 26% when administered with upadacitinib relative to when administered alone. ...
This phase 1, 2‐part, 2‐period, open‐label, drug‐drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once‐daily doses of upadacitinib extended‐release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUCinf) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin Cmax and AUCinf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The Cmax and AUCinf of the active metabolite ortho‐hydroxyatorvastatin remained unchanged. Administration of a single 5‐mg dose of rosuvastatin or a single 10‐mg dose of atorvastatin had no relevant effect on upadacitinib Cmax or area under the plasma concentration–time curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.
... Upadacitinib (RINVOQ; AbbVie, North Chicago, IL, USA) is an oral, smallmolecule JAK inhibitor that has greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2; upadacitinib has been approved for use in the USA, Europe, and other countries for the treatment of moderately or severely active rheumatoid arthritis and is under investigation for the treatment of other immunemediated diseases. 17 Results from a phase 2b study in patients with moderatetosevere atopic dermatitis found that once daily upadacitinib monotherapy (15 mg or 30 mg) was effica cious with a favourable benefit-risk profile compared with placebo, indicating the potential of upadacitinib as a treatment for patients with moderatetosevere atopic dermatitis. 18 Here, we report the primary results from two phase 3 trials of upadacitinib monotherapy, designed to assess the efficacy and safety of upadacitinib for the treatment of adolescents and adults with moderatetosevere atopic dermatitis. ...
Background:
Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Methods:
Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting.
Findings:
Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients).
Interpretation:
Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis.
Funding:
AbbVie.
... Under fasting conditions, peak plasma concentrations of upadacitinib were reached within 2 h of administration of the ER tablet [12]. Upadacitinib plasma exposures were doseproportional over the range of IR and ER doses evaluated in clinical studies; this encompassed doses ranging from 1 to 48 mg using the IR formulation and 7.5 to 45 mg using the ER formulation [11][12][13][14]. The bioavailability of the ER Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-019-0378-y) ...
Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro–in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.
Autoimmune diseases (AIDs) are a group of disorders in which the immune system attacks the body’s own tissues, leading to chronic inflammation and organ damage. These diseases are difficult to treat due to variability in drug PK among individuals, patient responses to treatment, and the side effects of long-term immunosuppressive therapies. In recent years, pharmacometrics has emerged as a critical tool in drug discovery and development (DDD) and precision medicine. The aim of this review is to explore the diverse roles that pharmacometrics has played in addressing the challenges associated with DDD and personalized therapies in the treatment of AIDs. Methods: This review synthesizes research from the past two decades on pharmacometric methodologies, including Physiologically Based Pharmacokinetic (PBPK) modeling, Pharmacokinetic/Pharmacodynamic (PK/PD) modeling, disease progression (DisP) modeling, population modeling, model-based meta-analysis (MBMA), and Quantitative Systems Pharmacology (QSP). The incorporation of artificial intelligence (AI) and machine learning (ML) into pharmacometrics is also discussed. Results: Pharmacometrics has demonstrated significant potential in optimizing dosing regimens, improving drug safety, and predicting patient-specific responses in AIDs. PBPK and PK/PD models have been instrumental in personalizing treatments, while DisP and QSP models provide insights into disease evolution and pathophysiological mechanisms in AIDs. AI/ML implementation has further enhanced the precision of these models. Conclusions: Pharmacometrics plays a crucial role in bridging pre-clinical findings and clinical applications, driving more personalized and effective treatments for AIDs. Its integration into DDD and translational science, in combination with AI and ML algorithms, holds promise for advancing therapeutic strategies and improving autoimmune patients’ outcomes.
Juvenile idiopathic arthritis (JIA) is the most prevalent pediatric rheumatic disease. While disease‐modifying antirheumatic drugs (DMARDs), especially biologics, have greatly transformed the management of JIA, there remain some unmet medical needs that require new treatment options. The objective of this work was to describe and apply a modeling and simulation approach to extrapolate upadacitinib efficacy from the adult diseases, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), to their respective pediatric diseases, polyarticular course JIA (pcJIA), and juvenile PsA (JPsA). A population pharmacokinetic model characterized upadacitinib pharmacokinetics in pediatric patients using data from two phase I studies in pediatric patients with pcJIA ( N = 51) or atopic dermatitis ( N = 33). Efficacy simulations were conducted using previously developed exposure–response models in adults with RA and PsA. Real‐world pcJIA and JPsA patient databases were leveraged to construct representative patient profiles for the targeted population. Following administration of the proposed weight‐based dosing regimen, the model‐predicted median upadacitinib plasma exposures in pediatric patients were within 20% of those in adult RA and PsA patients receiving the approved adult regimen. Simulations demonstrate that upadacitinib efficacy in pcJIA and JPsA is predicted to be non‐inferior to that in adults with RA or PsA, respectively. The results of this work enabled recent approvals of upadacitinib for the treatment of polyarticular JIA and JPsA in the United States. Upadacitinib safety in pediatrics is being further evaluated in ongoing clinical trials.
Upadacitinib, a selective Janus kinase inhibitor, is the first orally administered therapy approved for the treatment of Crohn's disease (CD). This work characterized the pharmacokinetics of upadacitinib in CD patients and evaluated the relationships between upadacitinib steady‐state plasma exposures and efficacy as well as safety parameters during the 12‐week induction and the 52‐week maintenance periods, to provide dosing recommendations for the treatment of CD. Upadacitinib pharmacokinetics in CD patients administered the extended‐release formulation were consistent with patient populations in other approved indications. None of the evaluated CD‐specific patient characteristics (e.g., disease location and prior gastrointestinal surgeries) had a meaningful impact on upadacitinib pharmacokinetics. Exposure–response analyses during 12‐week induction treatment showed that response across all evaluated efficacy end points were approaching a plateau at median plasma exposures associated with 45 mg QD. Analyses for the maintenance period demonstrated that 30 mg QD is predicted to provide an additional 8% to 10% benefit for endoscopic response and endoscopic remission compared with 15 mg QD in patients who failed biologics. The analyses for safety showed a statistically significant relationship between increasing upadacitinib plasma exposures and the percentage of patients experiencing >2 g/dL decrease in hemoglobin from Baseline during induction and showed shallow relationships for serious infections and herpes zoster during the maintenance period. These results demonstrated adequate absorption of the extended‐release formulation of upadacitinib in CD patients. The exposure–response analyses confirmed that 45 mg QD dose maximized efficacy as induction treatment and supported the selection of 15 mg QD or 30 mg QD as the maintenance doses.
Disease-modifying anti-rheumatic drugs (DMARDs) is a class of anti-rheumatic medicines that are frequently prescribed to patients suffering from rheumatoid arthritis (RA). Methotrexate, sulfasalazine, hydroxychloroquine, and azathioprine are examples of non-biologic DMARDs that are being used for alleviating pain and preventing disease progression. Biologic DMARDs (bDMARDs) like infliximab, rituximab, etanercept, adalimumab, tocilizumab, certolizumab pegol, and abatacept have greater effectiveness with fewer adverse effects in comparison to non-biologic DMARDs. This review article delineates the classification of DMARDs and their characteristic attributes. The poor aqueous solubility or permeability causes the limited oral bioavailability of synthetic DMARDs, while the high molecular weights along with the bulky structures of bDMARDs have posed few obstacles in their drug delivery and need to be addressed through the development of nanoformulations like cubosomes, nanospheres, nanoemulsions, solid lipid nanoparticles, nanomicelles, liposome, niosomes, and nanostructured lipid carrier. The main focus of this review article is to highlight the potential role of nanotechnology in the drug delivery of DMARDs for increasing solubility, dissolution, and bioavailability for the improved management of RA. This article also focusses on the different aspects of nanoparticles like their applications in biologics, biocompatibility, body clearance, scalability, drug loading, and stability issues.
Atopic dermatitis is an inflammatory skin disease, the prevalence of which has increased in the last decade. It affects all age groups, with adult involvement being a major focus of interest in recent years. The unmet needs of the disease, such as pruritus, sleep quality impairment and eczematous skin lesions, have undergone a therapeutic revolution following the commercialization of drugs such as JAK inhibitors. Upadacitinib, a selective JAK1 inhibitor, has been positioned by both clinical trial results and those observed in clinical practice as the fastest and most effective drug in reducing both pruritus and Eczema Area and Severity Index and validated Investigator Global Assessment. Although the safety profile may be initially alarming, it is advisable to update the actual data in this regard for proper management. New perspectives for upadacitinib in nonatopic comorbidities such as psoriasis and alopecia areata are beginning to be described, and interest in learning more about its peculiarities is growing.
The JAK signaling pathway plays a major role in the immunopathology of autoimmune diseases, including inflammatory bowel disease. JAK enzymes provide novel targets for rapidly effective inflammatory bowel disease therapy, particularly in ulcerative colitis. Upadacitinib is a targeted JAK1 inhibitor. In multiple phase III clinical trials, upadacitinib has demonstrated significant improvement in clinical and endoscopic outcomes and quality of life for patients with moderate-to-severe ulcerative colitis. In this drug evaluation we describe the role of the JAK signaling pathway in ulcerative colitis, the mechanism of action of upadacitinib and the current clinical evidence for its use in ulcerative colitis; we also review its safety and tolerability, including for special populations.
M10, a novel myricetin derivative, is an anti-inflammatory agent designed for treatment of colitis. Here, we aim to investigate its pharmacokinetic behavior and tissue distribution in a mouse model with colitis. Pharmacokinetics and tissue distribution of M10 and its metabolite myricetin were compared in normal mice and in dextran-sodium-sulfate (DSS)-induced colitis mice. The role of fecal microbiota was also analyzed during metabolism of M10 in vitro. After oral administration, M10 was very low in the plasma of both normal and diseased mice. However, both M10 and myricetin were mainly distributed in the gastrointestinal tract, including the stomach, colon and small intestine, in physiological and pathological conditions. Significantly, M10 and myricetin were found in higher levels in gastrointestinal tracts with inflamed tissues than in normal tissues of mice. An in vitro assay revealed that 80% of M10 was metabolized to myricetin via fecal microbiota. After oral administration, M10 was not absorbed into circulation but mainly distributed in the inflamed submucosal tissues of colitic mice, where it was metabolized into myricetin to prevent colitis development.
Introduction
Atopic dermatitis is one of the most prevalent chronic skin diseases. Topical therapies continue to be the mainstay of treatment but are limited by non-compliance and side-effects from inappropriate or long-term use. Systemic therapies including cyclosporin and dupilumab have been the treatments of choice for refractory cases. However, outcomes may remain less than satisfactory and cyclosporine use is further limited by nephrotoxicity.
Upadacitinib, an oral Janus kinase inhibitor, is widely used for treating rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis and has recently received approval for atopic dermatitis in the United States, Europe, Japan, and other countries. These approvals were based on results from several randomized controlled trials in which upadacitinib demonstrated better and faster response versus placebo or dupilumab.
Area covered
Therapies for atopic dermatitis are reviewed, with emphasis on drug profile, efficacy, and safety profile of upadacitinib for atopic dermatitis. In the review of the clinical trials, special focus is placed on efficacy in the Japanese population.
Expert opinion
Currently, there are several treatment options for atopic dermatitis refractory to topical therapies. However, appropriate utilization of Janus kinase inhibitors in clinical practice remains challenging, especially with regards to proper case selection, optimal timing, and appropriateness of use.
Janus Kinase (JAK), a nonreceptor protein tyrosine kinase, has emerged as an excellent target through research and development since its discovery in the 1990s. As novel small-molecule targeted drugs, JAK inhibitor drugs have been successfully used in the treatment of rheumatoid arthritis (RA), myofibrosis (MF) and ulcerative colitis (UC). With the gradual development of JAK targets in the market, JAK inhibitors have also received very considerable feedback in the treatment of autoimmune diseases such as atopic dermatitis (AD), Crohn's disease (CD) and graft-versus host disease (GVHD). This article reviews the research progress of JAK inhibitor drugs: introducing the existing JAK inhibitors on the market and some JAK inhibitors in clinical trials currently. In addition, the synthesis of various types of JAK inhibitors were summarized, and the effects of different drug structures on drug inhibition and selectivity.
Background
Systemic atopic dermatitis treatments that have acceptable safety are needed.
Objective
To evaluate the safety of the oral Janus kinase inhibitor upadacitinib in combination with topical corticosteroids (TCSs) for the treatment of atopic dermatitis.
Methods
In this phase 3, double-blind study (Rising Up), Japanese patients (12-75 years) with moderate-to-severe atopic dermatitis were randomized in a 1:1:1 ratio to receive 15 mg of upadacitinib + TCS, 30 mg of upadacitinib + TCS, or a placebo + TCS (rerandomized in a 1:1 ratio to receive either 15 or 30 mg of upadacitinib + TCS at week 16). Adverse events and laboratory data were assessed for safety.
Results
In 272 treated patients, the serious adverse event rates were similar for 15- and 30-mg upadacitinib + TCS at week 24 (15 mg, 56%; 30 mg, 64%) but greater than those for placebo + TCS (42%). Acne (all mild or moderate; none leading to discontinuation) occurred more frequently with upadacitinib + TCS (15 mg, 13.2%; 30 mg, 19.8%) than with placebo + TCS (5.6%). Furthermore, herpes zoster infection (4.4% vs 0%), anemia (1.1% vs 0%), neutropenia (4.4% vs 1.1%), and creatine phosphokinase elevations (2.2% vs 1.1%) occurred more frequently with 30-mg upadacitinib + TCS than with 15-mg upadacitinib + TCS; none of these events were reported with placebo + TCS. No thromboembolic events, malignancies, gastrointestinal perforations, active tuberculosis, or deaths occurred.
Limitations
The limitations included a small sample size and short observation period as well as nongeneralizability of the results beyond Japanese populations.
Conclusions
The results were generally consistent with those of previous reports; no new safety risks were detected.
INTRODUCTION
: Ulcerative colitis (UC) is an inflammatory disease of the large intestine. Progress in preclinical therapeutic target discovery and clinical trial design has resulted in the approval of new therapies. Nonetheless, remission rates remain (below 30%) thus underlining the need for novel, more effective therapies.
AREAS COVERED
: This paper reviews current experimental techniques available for drug testing in intestinal inflammation and examines new therapies in clinical development for the treatment of UC. The authors searched the literature for “ulcerative colitis” AND “preclinical” OR “drug target/drug name” (i.e., infliximab, vedolizumab, IL-12, IL-23, JAK, etc.). Studies that included preclinical in vivo or in vitro experiments are discussed. The clinicaltrial.gov site was searched for “ulcerative colitis” AND “Recruiting” OR “Active, not recruiting” AND “Interventional (Clinical Trial)” AND “early phase 1” OR “phase 1” OR “phase 2” OR “phase 3”.
EXPERT OPINION
: Using in vivo, ex vivo, and/or in vitro models could increase the success rates of drugs moving to clinical trials, and hence increase the efficiency of this costly process. Selective JAK1 inhibitors, S1P modulators, and anti-p19 antibodies are the most promising options to improve treatment effectiveness. The development of drugs with gut-restricted exposure may provide increased efficacy and an improved safety.
Upadacitinib plasma concentrations, efficacy, and safety data from 216 subjects with moderately‐to‐severely active Crohn’s disease (CD) from the 16‐week induction period of CELEST study were analyzed to characterize upadacitinib exposure‐response relationships in CD. Subjects in CELEST received either placebo or upadacitinib (3, 6, 12, 24 mg twice‐daily [BID] or 24 mg once‐daily [QD]). Exposure‐response models were developed and utilized to simulate efficacy of induction doses of the IR and ER formulations. Upadacitinib exposures associated with 18 to 24 mg BID (IR formulation) or 45 to 60 mg QD (ER formulation) are estimated to have greater efficacy during 12‐week induction in CD patients compared to lower doses. No exposure‐response relations were observed with decreases in hemoglobin or lymphocytes at Week 16 or with herpes zoster infections, pneumonia, or serious infections during 16 weeks of treatment in this study. These analyses informed the selection of upadacitinib induction dose for Phase 3 studies in CD.
The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.
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Objective
To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1‐selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX).
Methods
In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally.
Results
At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28‐CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28‐CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib‐treated patients than placebo‐treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group).
Conclusion
Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib.
Background and Objectives
Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I–III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations.
Methods
Pharmacokinetic data from 4170 subjects taking IR doses of 1–48 mg and ER doses of 7.5–30 mg across 12 studies spanning phase I–III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks.
Results
A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration–time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration–time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60–100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure.
Conclusions
A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I–III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure–response relationship of upadacitinib.
Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice‐daily regimens of an immediate‐release (IR) formulation. The upadacitinib extended‐release (ER) formulation was developed to enable once‐daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once‐daily doses of the ER formulation in healthy subjects relative to single and multiple twice‐daily doses of the IR formulation. Increase in upadacitinib exposure was dose‐proportional over the evaluated 15‐ to 30‐mg ER dose range. Single 15‐ and 30‐mg ER doses provided equivalent AUC0–inf compared with single 12‐ and 24‐mg IR doses, respectively. A high‐fat breakfast increased upadacitinib ER Cmax and AUC0–inf by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once‐daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC0–24, comparable Cmax and Cmin, and a fluctuation index over a 24‐hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15‐ and 30‐mg doses of the ER formulation in the phase 3 trials in RA.
Background and objectives:
Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure.
Methods:
Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations.
Results:
A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight.
Conclusions:
Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure.
Trial registration:
ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.
Objective:
To compare the efficacy and safety of ABT-494, a selective Janus kinase 1 inhibitor, with placebo, in patients with moderate-to-severe rheumatoid arthritis (RA) and inadequate response (IR) to methotrexate.
Methods:
In this 12-week, randomized, double-blind, study, 300 patients on background methotrexate were randomized equally to immediate-release ABT-494 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo. The primary efficacy endpoint was the proportion of patients achieving an ACR20 response (LOCF) at Week 12.
Results:
At Week 12, ACR20 responses were higher with ABT-494 (62%, 68%, 80%, 64%, 76% for 3, 6,12,18 and 24 mg doses) versus placebo (46%) (NRI, P<0.05 for 6, 12 and 24 mg doses), with a significant dose-response relationship among all ABT-494 doses (P<0.001). ACR50 and ACR70 responses and changes in DAS28(CRP) [ΔDAS28(CRP)] were significantly higher for all ABT-494 doses (except 12 mg for ACR70) versus placebo. Onset of action was rapid, with significant differences at Week 2 in ACR20 response (P≤0.027) and ΔDAS28(CRP) for all doses versus placebo. Incidence of AEs was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 12 mg. There were dose-dependent increases, but an unchanged ratio of LDL-C:HDL-C through Week 12. Mean hemoglobin remained stable at lower doses but decreases were observed at higher doses.
Conclusions:
This study evaluated a broad dose range in methotrexate-IR patients. ABT-494 demonstrated efficacy, with a similar safety and tolerability profile to other JAK inhibitors. No new AEs were identified. This article is protected by copyright. All rights reserved.
Background
Atopic dermatitis (AD) is associated with multiple comorbid conditions, such as asthma and food allergy. We sought to determine the impact of eczema severity on the development of these disorders and other non-atopic comorbidities in AD. Methods
We used the 2007 National Survey of Children's Health, a prospective questionnaire-based study of a nationally representative sample of 91,642 children aged 0-17yr. Prevalence and severity of eczema, asthma, hay fever and food allergy, sleep impairment, healthcare utilization, recurrent ear infections, and visual and dental problems were determined. ResultsIn general, more severe eczema is correlated with poorer overall health, impaired sleep, and increased healthcare utilization, including seeing a specialist, compared with children with mild or moderate disease (Rao-Scott chi-squared test, p<0.0001). Severe eczema was associated with a higher prevalence of comorbid chronic health disorders, including asthma, hay fever, and food allergies (p<0.0001). In addition, the severity of eczema was directly related to the severity of the comorbidities. These associations remained significant in multivariate logistic regression models that included age, sex, and race/ethnicity. Severe eczema was also associated with recent dental problems, including bleeding gums (p<0.0001), toothache (p=0.0004), but not broken teeth (p=0.04) or tooth decay (p=0.13). Conclusions
These data indicate that severe eczema is associated with multiple comorbid chronic health disorders, impaired overall health, and increased healthcare utilization. Further, these data suggest that children with eczema are at risk of decreased oral health. Future studies are warranted to verify this novel association.
Janus kinases (Jaks) play an important role in signal transduction via cytokine and growth factor receptors. A targeted inactivation of Jak2 was performed. Jak2-/- embryos are anemic and die around day 12.5 postcoitum. Primitive erythrocytes are found, but definitive erythropoiesis is absent. Compared to erythropoietin receptor-deficient mice, the phenotype of Jak2 deficiency is more severe. Fetal liver BFU-E and CFU-E colonies are completely absent. However, multilineage hematopoietic stem cells (CD34low, c-kit(pos)) can be found, and B lymphopoiesis appears intact. In contrast to IFNalpha stimulation, Jak2-/- cells do not respond to IFNgamma. Jak2-/- embryonic stem cells are competent for LIF signaling. The data provided demonstrate that Jak2 has pivotal functions for signal transduction of a set of cytokine receptors required in definitive erythropoiesis.
The Genetic Counseling Definition Task Force of the National Society of Genetic Counselors (NSGC) developed the following definition of genetic counseling that was approved by the NSGC Board of Directors:
Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:
•Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
•Education about inheritance, testing, management, prevention, resources and research.
•Counseling to promote informed choices and adaptation to the risk or condition.
The definition was approved after a peer review process with input from the NSGC membership, genetic professional organizations, the NSGC legal counsel, and leaders of several national genetic advocacy groups.
INTRODUCTION
We assessed efficacy/safety of upadacitinib (UPA) in a ph 2b induction study (part 1) in pts with moderately-to-severely active ulcerative colitis (UC). Additional Pts were enrolled in part 2. We present the efficacy and safety of the combined results of part 1 and part 2
METHODS
Adults with moderately-to-severely active UC (Adapted Mayo Score 5–9 points and centrally-read endoscopy subscore 2–3) were randomised 1:1:1:1:1 to receive extended-release UPA7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 wks (N = 250). In part 2, 132 pts were randomised to UPA30 or 45 mg QD with 1:1 allocation for 8 weeks. Pairwise comparisons between UPA and PBO for primary endpoint of clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and ranked secondary endpoints were conducted using Cochran-Mantel-Haenszel test stratified by previous biologic use, BL corticosteroid use, and BL Adapted Mayo score. No multiplicity adjustments were applied. Non-responder imputation was used for missing values in 13% of pts. Treatment emergent adverse events (AEs) were reported from first dose of study drug to up to 30 days after last dose.
RESULTS
A total 382 pts were randomised with mean (SD) age of 42.7 (14.3) yrs and disease duration of 8.4 (7.4) yrs. Primary endpoint of clinical remission, and secondary endpoints of endoscopic improvement, clinical response per Adapted Mayo score, clinical response per Partial Mayo score, endoscopic remission, and histologic improvement were significantly higher with UPA doses ≥30 mg QD vs PBO (Table 1). Incidences of AEs were similar across UPA groups and numerically higher in PBO group. Rates of serious AEs were 10.9%, 0%, 4.1%, 4.3% and 4.9% for PBO and UPA 7.5, 15, 30, and 45 mg QD, respectively. Serious infections occurred in pts receiving PBO (4.3%, n = 2), 15 mg QD (2.0%, n = 1), 30 mg QD (0.9%, n = 1), and 45 mg QD (1.6%, n = 2). One case of herpes zoster and pulmonary embolism (PE)/deep vein thrombosis (DVT) with UPA 45 mg QD were reported. PE/DVT was reported 26 days after study drug discontinuation due to UC worsening and hospitalization. No deaths were reported.
CONCLUSION
In this combined analysis, primary and ranked secondary endpoints consistently met statistical significance with UPA doses ≥ 30 mg QD vs PBO in pts with moderately-to-severely active UC. These results are consistent with part 1 intention-to-treat analysis. 1,2 UPA was well-tolerated and no new safety signals were identified.
Background
Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate.
Methods
SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of upadacitinib 15 mg or 30 mg or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951.
Findings
Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35–48) in the continued methotrexate group, 147 (68%) of 217 patients (62–74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65–77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14–25) in the continued methotrexate group, 97 (45%) of 217 (38–51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46–60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study.
Interpretation
Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies.
Funding
AbbVie Inc, USA.
Background:
Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs).
Methods:
This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426.
Findings:
Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58-70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60-73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29-42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42-55) patients receiving upadacitinib 15 mg and 105 (48%; 41-55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12-22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial.
Interpretation:
Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms.
Funding:
AbbVie Inc.
Background:
Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, have shown safety and efficacy in the treatment of patients with active rheumatoid arthritis. We did this study to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs).
Methods:
We did this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries. Patients were aged 18 years or older, had active rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, and were receiving concomitant background conventional synthetic DMARDS (csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 onwards. The two separate primary endpoints were the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and the proportion of patients achieving a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy and safety analyses were done in the modified intention-to-treat population of all patients who received at least one dose of study drug. Data are presented up to week 24 of this ongoing study. The trial is registered with ClinicalTrials.gov (NCT02706847).
Findings:
Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 patients had received one previous bDMARD, 137 (28%) had received two, and 125 (25%) had received at least three; 451 (91%) patients completed treatment up to week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, ACR20 was achieved by 106 (65%; 95% CI 57-72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49-64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22-35) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 36-51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35-50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9-20) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall numbers of patients with adverse events were similar for the placebo group (95 [56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common adverse events occurring in at least 5% of patients in any treatment group were upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis (ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse events was higher in the upadacitinib 30 mg group (12 [7%]) than in the upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported in patients receiving placebo. More patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo.
Interpretation:
Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis.
Funding:
AbbVie Inc.
Tofacitinib is the first Janus kinase (JAK) inhibitor commercially approved for the treatment of rheumatoid arthritis. This compound and a number of other JAK inhibitors are currently being tested in phase II and III trials for the treatment of a variety of autoimmune inflammatory diseases. Whereas a characteristic safety profile is emerging for some JAK inhibitors, differences between individual agents might emerge on the basis of distinct potency against their molecular targets. Similarly to biological therapy, JAK inhibition can lead to serious and opportunistic infections, and viral infections seem to be particularly frequent. Although no malignancy signals have been identified to date, long-term follow-up and further research are needed to understand the risk of malignancy associated with these compounds. As is the case for biologic agents, vaccination is important to mitigate the risks of these emerging therapies.
Objective:
To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with placebo, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to ≥1 anti-tumor necrosis factor (TNF) therapy.
Methods:
In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 patients with ≥1 prior anti-TNF therapy on a stable methotrexate dose were randomized equally to immediate-release ABT-494 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 12.
Results:
At Week 12, significantly more patients in the ABT-494 groups (53-71%) versus placebo (34%) achieved an ACR20 response (NRI, P<0.05), with a dose-response relationship among all ABT-494 doses (P<0.001). ACR50/70 response rates were significantly higher in the ABT-494 groups (35-42% and 22-26%) versus placebo (ACR50, 16% and ACR70, 4%). Changes in DAS28(CRP) [ΔDAS28(CRP)] were significantly greater for all doses of ABT-494 versus placebo (P≤0.001). Onset of action was rapid, with significant differences versus placebo at Week 2, in ACR20 and ΔDAS28(CRP) (P≤0.001 for 6-18 mg). The most frequent AEs were headache, nausea, upper respiratory and urinary tract infections. Infection rates were higher at higher doses of ABT-494, but none were serious. No deaths were reported on ABT-494.
Conclusions:
In patients with an inadequate response or intolerance to anti-TNF therapy, ABT-494 added onto methotrexate showed rapid, dose-dependent improvements in RA signs and symptoms, with similar safety and tolerability to drugs of this class. No new AEs were identified. This article is protected by copyright. All rights reserved.
Background:
ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation.
Methods:
ABT-494 single (1-48 mg or placebo; n = 56) and multiple (3-24 mg or placebo twice daily for 14 days; n = 44) doses in healthy subjects, as well as multiple doses (3-24 mg or placebo twice daily for 27 days; n = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed.
Results:
ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6-16 h and a functional half-life, calculated from maximum observed plasma concentration (C max) to trough plasma concentration (C trough) ratio at steady state, of 3-4 h. ABT-494 exposure was approximately dose proportional over the 3-36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14-25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed.
Conclusions:
The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn's disease.
Trial registration:
ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.
X-ray mammography of the compressed breast is well recognized as the “gold standard” for early detection of breast cancer, but its performance is not ideal. One limitation of screening mammography is tissue superposition, particularly for dense breasts. Since 2001, several research groups in the USA and in the European Union have developed computed tomography (CT) systems with digital detector technology dedicated to x-ray imaging of the uncompressed breast (breast CT or BCT) for breast cancer screening and diagnosis. This CT technology—tracing back to initial studies in the 1970s—allows some of the limitations of mammography to be overcome, keeping the levels of radiation dose to the radiosensitive breast glandular tissue similar to that of two-view mammography for the same breast size and composition. This paper presents an evaluation of the research efforts carried out in the invention, development, and improvement of BCT with dedicated scanners with state-of-the-art technology, including initial steps toward commercialization, after more than a decade of R&D in the laboratory and/or in the clinic. The intended focus here is on the technological/engineering aspects of BCT and on outlining advantages and limitations as reported in the related literature. Prospects for future research in this field are discussed.
Background Anti-cytokine therapies have become the mainstay of treatment for rheumatoid arthritis (RA) disease symptoms and can arrest disease progression. Despite numerous treatment options there are still many RA patients who fail to experience substantial decreases in disease activity. Recently, Jak kinase blockade was shown clinically to be effective in managing disease and in some cases achieving remission. However, these first generation Jak inhibitors have failed to meet expectations due to dose-limiting tolerability and safety issues. ABT-494 is a second generation Jak kinase inhibitor with high selectivity for Jak1 thereby minimizing the potential for side effects related to Jak2 and Jak3 inhibition. Here we describe preclinical and early clinical data that suggest ABT-494 has potential to address some of the current unmet medical needs of RA patients.
Methods ABT-494 was engineered for increased selectivity for Jak1 using structural predictions that indicated the potential for differential binding interactions outside the ATP-binding active site of Jak1 but not Jak2. The efficacy and selectivity of ABT-494 were tested in a battery of relevant cellular and in vivo pharmacology assays including bone marrow colony formation, adjuvant induced arthritis (AIA), erythropoietin induced reticulocyte deployment and NK/NKT cell suppression. The potency of ABT-494 in a variety of complementary pharmacodynamic assays was also assessed at multiple dosages in healthy human subjects administered orally for 14 days.
Results ABT-494 demonstrates approximately 74 fold selectivity for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. ABT-494 is a potent inhibitor of inflammation and bone loss in rat AIA and, compared to Tofacitinib, spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats. When dosed orally for 14 days in healthy human subjects ABT-494 did not decrease reticulocyte or NK cell counts at predicted efficacious doses consistent with its pharmacodynamic properties in rats.
Conclusions ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models. Preliminary evidence suggests that pharmacodynamic properties of ABT-494 are consistent between those observed in rodent models and in healthy human subjects. Taken together, these encouraging observations support further testing of ABT-494 in RA patients in Phase II randomized placebo controlled trials and indicate it may have increased potential to address patient needs over existing agents.
Disclosure of Interest : J. Voss Employee of: AbbVie, C. Graff Employee of: AbbVie, A. Schwartz Employee of: AbbVie, D. Hyland Employee of: AbbVie, M. Argiriadi Employee of: AbbVie, H. Camp Employee of: AbbVie, L. Dowding Employee of: AbbVie, M. Friedman Employee of: AbbVie, K. Frank Employee of: AbbVie, J. George Employee of: AbbVie, E. Goedken Employee of: AbbVie, G. Lo Schiavo: None declared, M. Morytko Employee of: AbbVie, R. O'Brien Employee of: AbbVie, R. Padley Employee of: AbbVie, M. Rozema Employee of: AbbVie, M. Rosebraugh Employee of: AbbVie, K. Stewart Employee of: AbbVie, G. Wallace Employee of: AbbVie, N. Wishart Employee of: AbbVie, A. Murtaza Employee of: AbbVie, L. Olson Employee of: AbbVie
DOI 10.1136/annrheumdis-2014-eular.3823
Introduction:
The JAK kinases are a family of four tyrosine receptor kinases that play a pivotal role in cytokine receptor signalling pathways via their interaction with signal transducers and activators of transcription proteins. Selective inhibitors of JAK kinases are viewed as of considerable potential as disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis.
Areas covered:
This article provides a review of the clinical development and available clinical results for those JAK inhibitors currently under investigation. Phase II data for four JAK inhibitors (baricitinib, decernotinib, filgotinib and INCB-039110) are contrasted with that reported for the recently approved JAK inhibitor tofacitinib. The preclinical data on these, in addition to peficitinib, ABT-494, INCB-047986 and AC-410 are also discussed, as are some of the inhibitors in preclinical development.
Expert opinion:
JAK inhibitors are effective in the treatment of rheumatoid arthritis as evidenced by several inhibitors enabling the majority of treated patients to achieve ACR20 responses, with baricitinib and INCB-039110 both effective when administered once daily. JAK inhibitors differ in isoform specificity profiles, with good efficacy achievable by selective inhibition of either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib). It remains to be seen what selectivity provides the optimal side-effect profile and to what extent inhibition of JAK2 should be avoided.
Cytokines are critical for normal cell growth and immunoregulation but also contribute to growth of malignant cells and drive immune-mediated disease. A large subset of immunoregulatory cytokines uses the type I and type II cytokine receptors and pharmacological targeting of these cytokines/cytokines receptors has proven to be efficacious in treating immune and inflammatory diseases. These receptors rely on Janus family of kinases (Jaks) for signal transduction. Recently the first Jak inhibitor (jakinib) has been approved by the FDA and a second has been recommended for approval. Many other Jakinibs are likely to follow and in this brief review, we will discuss the state-of-the art of this new class of pharmacological agents.
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20(th) anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease.
Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50% of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0% of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal.
The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.
The Janus family tyrosine kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway is broadly used by interferons and type I cytokines. These cytokines and interferons activate Janus family tyrosine kinases (Jak kinases), which in turn phosphorylate and thereby activate STAT proteins. Before activation, STAT proteins are cytosolic proteins; after activation, however, they are translocated to the nucleus where they function as transcription factors. This review summarizes salient features of the Jak-STAT pathway and focuses on the functional role of the different Jak kinases and STATs in vivo.
Pharmacokinetic data consist of drug concentration measurements, as well as reports of some measured concentrations being below the quantification limit of the assay (BQL). A pharmacokinetic model may befit to these data, and for this purpose, the BQL observations must be either discarded or handled in a special way. In this paper, seven methods for dealing with BQL observations are evaluated. Both single-subject and population data are simulated from a one-compartment model. A moderate amount of data is simulated for each individual. The actual cv of concentration measurements at the quantification limit is assumed to be no greater than 20%, in accord with the FDA Guidance. The results of this paper should be interpreted in this context. The methods include handling BQL observations as fixed-point censored observations, i.e., by using the likelihoods that these observations are in fact BQL. This method is shown to have some overall statistical advantage. However, the gain in using this method over that of simply discarding the BQL observations is not always much, and this is especially so when the frequency of BQL observations is small. Some simple methods entailing (i) replacing one or more BQL observations with the value 0, or (ii) replacing them with the value QL/2, where QL is the quantification limit, are also included. The first of these two approaches should not be used With population data, use of the second approach can result in some noticeably improved estimation of the typical value of a parameter, but then there is also marked degradation in the estimation of the population variance of the parameter.
Gastrointestinal (GI) and liver diseases inflict a heavy economic burden. Although the burden is considerable, current and accessible information on the prevalence, morbidity, and cost is sparse. This study was undertaken to estimate the economic burden of GI and liver disease in the United States for use by policy makers, health care providers, and the public.
Data were extracted from a number of publicly available and proprietary national databases to determine the prevalence, direct costs, and indirect costs for 17 selected GI and liver diseases. Indirect cost calculations were purposefully very conservative. These costs were compared with National Institutes of Health (NIH) research expenditures for selected GI and liver diseases.
The most prevalent diseases were non-food-borne gastroenteritis (135 million cases/year), food-borne illness (76 million), gastroesophageal reflux disease (GERD; 19 million), and irritable bowel syndrome (IBS; 15 million). The disease with the highest annual direct costs in the United States was GERD (5.8 billion), colorectal cancer (3.1 billion). The estimated direct costs for these 17 diseases in 1998 dollars were 22.8 billion. The estimated direct costs for all digestive diseases were 676 million in 2000.
GI and liver diseases exact heavy economic and social costs in the United States. Understanding the prevalence and costs of these diseases is important to help set priorities to reduce the burden of illness.
Although the incidence and prevalence of ulcerative colitis and Crohn's disease are beginning to stabilize in high-incidence areas such as northern Europe and North America, they continue to rise in low-incidence areas such as southern Europe, Asia, and much of the developing world. As many as 1.4 million persons in the United States and 2.2 million persons in Europe suffer from these diseases. Previously noted racial and ethnic differences seem to be narrowing. Differences in incidence across age, time, and geographic region suggest that environmental factors significantly modify the expression of Crohn's disease and ulcerative colitis. The strongest environmental factors identified are cigarette smoking and appendectomy. Whether other factors such as diet, oral contraceptives, perinatal/childhood infections, or atypical mycobacterial infections play a role in expression of inflammatory bowel disease remains unclear. Additional epidemiologic studies to define better the burden of illness, explore the mechanism of association with environmental factors, and identify new risk factors are needed.
A maintenance and long-term extension study of the efficacy and safety of upadacitinib (ABT-494) in subjects with Crohn's disease who completed the studies M14-431 or M14-433
- Abbvie
A study of the efficacy and safety of upadacitinib (ABT-494) in subjects with moderately to severely active crohn's disease who have inadequately responded to or are intolerant to conventional therapies but have not failed biologic therapy
- Abbvie
Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study u-achieve
- Sandbornw Ghoshs Panesj
A study of the efficacy and safety of upadacitinib (ABT-494) in subjects with moderately to severely active Crohn's disease who have inadequately responded to or are intolerant to biologic therapy
- Abbvie