Publications (17)152.93 Total impact
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Article: Tofacitinib (CP-690,550) in patients with rheumatoid arthritis on methotrexate: 12-Month data from a 24-month Phase 3 randomized radiographic study.
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ABSTRACT: BACKGROUND: The purpose of this 24-month Phase 3 study is to examine structural preservation with tofacitinib in patients with RA with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS: In this double-blind, parallel-group, placebo-controlled study (NCT00847613), patients on background MTX were randomized 4:4:1:1 to: tofacitinib 5 mg twice daily (BID); tofacitinib 10 mg BID; placebo→tofacitinib 5 mg BID; placebo→tofacitinib 10 mg BID. At Month 3, non-responder placebo patients were blindly advanced to tofacitinib as indicated above; remaining placebo patients were advanced at six months. Primary efficacy endpoints were all analyzed in a step-down procedure. RESULTS: Primary efficacy endpoints: ACR20 response rates (Month 6) for tofacitinib 5 and 10 mg BID were higher than placebo (51.5% and 61.8%, respectively, versus 25.3%; both p<0.0001); least squares (LS) mean changes in mTSS (Month 6) for 5 and 10 mg BID were 0.12 (p=0.0792) and 0.06 (p≤0.05), respectively, versus placebo, 0.47; LS mean changes in HAQ-DI (Month 3) for 5 and 10 mg BID were -0.40 (significance not declared due to step-down procedure) and -0.54 (p<0.0001), respectively, versus placebo, -0.15; DAS28-4(ESR)<2.6 rates (Month 6) for 5 and 10 mg BID were 7.2% (significance not declared due to step-down procedure) and 16.0% (p<0.0001), respectively, versus placebo, 1.6%. The safety profile was consistent with previous studies. CONCLUSIONS: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves RA disease activity in patients with RA on MTX. © 2012 American College of Rheumatology.Arthritis & Rheumatism 01/2013; · 7.87 Impact Factor -
Article: Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.
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ABSTRACT: BACKGROUND: Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. METHODS: We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28<2·6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. FINDINGS: At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06-28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45-34·92]; p<0·0001) for tofacitinib 10 mg twice a day versus 24·4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0·43 ([-0·36 to -0·15]; p<0·0001) for 5 mg twice a day and -0·46 ([-0·38 to -0·17]; p<0·0001) for 10 mg twice a day tofacitinib versus -0·18 for placebo; DAS28<2·6 rates were 6·7% (eight of 119; [0-10·10]; p=0·0496) for 5 mg twice a day tofacitinib and 8·8% (11 of 125 [1·66-12·60]; p=0·0105) for 10 mg twice a day tofacitinib versus 1·7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4·9%), nasopharyngitis (11 of 267; 4·1%), headache (11 of 267; 4·1%), and urinary tract infection (eight of 267; 3·0%) across tofacitinib groups, and nausea (nine of 132; 6·8%) in the placebo group. INTERPRETATION: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. FUNDING: Pfizer.The Lancet 01/2013; · 38.28 Impact Factor -
Article: Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.
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ABSTRACT: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).New England Journal of Medicine 08/2012; 367(6):508-19. · 53.30 Impact Factor -
Article: Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data.
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ABSTRACT: • Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate. • The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib. To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)). In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region. These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.British Journal of Clinical Pharmacology 01/2012; 74(1):109-15. · 2.96 Impact Factor -
Article: A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone.
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ABSTRACT: To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inadequate response to MTX monotherapy. In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. At week 12, ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P ≤ 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment-emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks.Arthritis & Rheumatism 10/2011; 64(4):970-81. · 7.87 Impact Factor -
Article: Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.
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ABSTRACT: To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.Arthritis & Rheumatism 09/2011; 64(3):617-29. · 7.87 Impact Factor -
Article: Dosing celecoxib in pediatric patients with juvenile rheumatoid arthritis.
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ABSTRACT: The objective was to derive dosing recommendations for the use of celecoxib in patients with juvenile rheumatoid arthritis (JRA) using pharmacokinetic (PK) and exposure-response data. PK and efficacy data from a randomized, double-blind, 12-week study of celecoxib dosed at 3 and 6 mg/kg twice a day (bid) as an investigational suspension formulation in 152 JRA patients aged 2 to 17 years, PK data from 36 adult RA patients, and relative bioavailability data in healthy adults comparing suspension or capsule sprinkles with the commercial capsule were analyzed. Typical oral clearance (L/h) values were 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared with a 70-kg patient. Longitudinal, logistic pharmacodynamic models incorporating linear effects of dose/area under the plasma concentration-time curve (AUC) over 0 to 12 hours (AUC(0-12)) suggested that the percentage of responders increased with celecoxib exposure. Systemic exposures (AUC) were similar for the suspension, capsule sprinkles, and intact capsule. Administration of a 50-mg bid capsule (or sprinkles) for patients weighing 10 to 25 kg and 100 mg bid for patients >25 kg was predicted to yield similar exposures and response rates as those observed in the JRA trial. Doses and dosage forms not studied in the JRA trial were approved based on the results of this analysis.The Journal of Clinical Pharmacology 08/2011; 52(8):1134-49. · 2.91 Impact Factor -
Article: Estimating transformations for repeated measures modeling of continuous bounded outcome data.
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ABSTRACT: Continuous bounded outcome data are unlikely to meet the usual assumptions for mixed-effects models of normally distributed and independent subject-specific and residual random effects. Additionally, overly complicated model structures might be necessary to account adequately for non-drug (time-dependent) and drug treatment effects. A transformation strategy with a likelihood component for censoring is developed to promote the simplicity of model structures and to improve the plausibility of assumptions on the random effects. The approach is motivated by Health Assessment Questionnaire Disability Index (HAQ-DI) data from a study in subjects with rheumatoid arthritis and is evaluated using a simulation study.Statistics in Medicine 04/2011; 30(9):935-49. · 1.88 Impact Factor -
Article: A supratherapeutic dose of the Janus kinase inhibitor tasocitinib (CP-690,550) does not prolong QTc interval in healthy participants.
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ABSTRACT: Tasocitinib (CP-690,550), a selective inhibitor of the Janus kinase (JAK) family, is being developed for the treatment of several autoimmune diseases and prevention of allograft rejection. The aim of this study was to characterize the effect of tasocitinib on QT interval. Sixty male and female healthy adults were enrolled in a single-dose, randomized, 3-period, crossover study of a supratherapeutic dose of tasocitinib (100 mg), placebo, and moxifloxacin 400 mg. Triplicate electrocardiograms were performed at predose baseline and serially over 24 hours postdose in each treatment period. The upper limits of the 2-sided 90% confidence intervals (CIs) for the difference in QTc interval, corrected using Fridericia correction (QTcF), between tasocitinib and placebo were less than 5 ms at all time points. Concentration-QTcF analysis showed that the predicted mean change (90% CI) in QTcF at the observed mean C(max) was -0.12 (-1.18, 0.94) ms. For moxifloxacin, mean (90% CI) estimates of the change in QTcF from placebo were 11.3 (9.4, 13.1) and 12.5 (10.7, 14.4) ms at 2 and 4 hours, respectively, thereby establishing study sensitivity. A single supratherapeutic dose of tasocitinib 100 mg was well tolerated and not associated with QTc prolongation.The Journal of Clinical Pharmacology 12/2010; 51(9):1256-63. · 2.91 Impact Factor -
Article: Population pharmacokinetic analysis of mycophenolic acid coadministered with either tasocitinib (CP-690,550) or tacrolimus in adult renal allograft recipients.
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ABSTRACT: Tasocitinib (CP-690,550) is an orally active Janus kinase inhibitor that is in development for prophylaxis of acute rejection after kidney transplantation and for the treatment of select autoimmune diseases. The current study was conducted to evaluate the systemic exposure of mycophenolic acid (MPA) in de novo kidney transplant patients when coadministered with tasocitinib compared with exposure in patients receiving tacrolimus, which has no effect on MPA pharmacokinetics. Plasma MPA concentrations were obtained from 17 adult patients who received either 15 mg or 30 mg tasocitinib twice daily (eight patients) or tacrolimus (nine patients) after kidney transplantation. All patients also received concomitant mycophenolate mofetil, prednisone, and basiliximab induction. The median mycophenolate mofetil dose was 1000 mg twice daily. A two-compartment population pharmacokinetic model estimating oral clearance, between-patient variability in oral clearance, central volume of distribution, and residual variability in combination with historical estimates of first-order absorption rate constant, intercompartmental clearance, and peripheral volume of distribution adequately described the sparse MPA data. Based on individual estimates oral clearance from the population pharmacokinetic model, mean steady-state area under the concentration-time curve values for a mycophenolate mofetil dose of 1000 mg twice daily were 63 mg·hr/L (22%) and 59 mg·hr/L (36%) for the tasocitinib and tacrolimus groups, respectively. These results indicate that tasocitinib does not influence systemic MPA exposure.Therapeutic drug monitoring 10/2010; 32(6):778-81. · 2.43 Impact Factor -
Article: Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes.
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ABSTRACT: CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions. CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2 g dl(-1)) were observed, although decreases of WBC to less than 1000 per mm(3) were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.Best practice & research. Clinical rheumatology 08/2010; 24(4):513-26. · 2.90 Impact Factor -
Article: A semi-mechanistic model of CP-690,550-induced reduction in neutrophil counts in patients with rheumatoid arthritis.
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ABSTRACT: CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE(h), ktr(h), gamma, and k(circ)), disease effect parameters (DIS), and drug effect parameters (k(off) and k(D)). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.The Journal of Clinical Pharmacology 10/2009; 50(6):679-87. · 2.91 Impact Factor -
Article: The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo.
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ABSTRACT: To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.Arthritis & Rheumatism 07/2009; 60(7):1895-905. · 7.87 Impact Factor -
Article: Effect of CP-690,550, an orally active janus kinase inhibitor, on renal function in healthy adult volunteers.
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ABSTRACT: CP-690,550 is a Janus kinase inhibitor being developed to prevent allograft rejection and treat several autoimmune diseases. This study examines the effect of multiple doses of CP-690,550 on renal function in healthy volunteers. Thirty-four volunteers are randomized in a 2:1 ratio in a double-blinded manner to receive CP-690,550 15 mg twice daily or placebo twice daily for 14 days. Volunteers are confined in-house to receive a controlled regimen of water intake and sodium intake of 4 to 5 g/d. The effect of CP-690,550 on glomerular filtration rate (GFR) is measured by iohexol serum clearance, effective renal plasma flow (ERPF) by para-aminohippuric acid (PAH) urinary clearance, and creatinine clearance by 24-hour urine collection on day 1 (predose) and day 15. Steady-state pharmacokinetics and tolerability are assessed. Comparing the day 15 and day 1 (predose) values shows that geometric mean ratios for iohexol serum clearance, PAH urinary clearance, and creatinine clearance are 0.995, 0.925, and 0.948, respectively. When adjusted for the corresponding placebo day ratios, the geometric mean ratios are 1.09, 0.978, and 1.05, respectively. CP-690,550 is well tolerated. These findings indicate that CP-690,550 does not affect GFR, ERPF, or creatinine clearance in healthy volunteers.The Journal of Clinical Pharmacology 05/2009; 49(4):423-9. · 2.91 Impact Factor -
Article: A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis.
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ABSTRACT: To compare the efficacy and safety of celecoxib and naproxen in children with juvenile rheumatoid arthritis (JRA). In this multicenter, randomized, double-blind, noninferiority study, subjects with JRA were randomized to receive a target dose of celecoxib 3 mg/kg bid or 6 mg/kg bid, or a target dose of naproxen 7.5 mg/kg bid for 12 weeks (maximum allowed dose=600 mg total daily dose). The primary efficacy measure was the percentage of responders at Week 12 attaining the American College of Rheumatology pediatric 30% improvement criterion (ACR Pediatric-30). Both celecoxib doses were at least as effective as naproxen at Week 12 [ACR Pediatric-30 treatment differences: celecoxib 3 mg/kg bid-naproxen=1.36% (95% CI -13.08 to 15.80); celecoxib 6 mg/kg bid-naproxen=13.02% (95% CI -0.22 to 26.25)]. Celecoxib 6 mg/kg bid had a numerically higher response rate than celecoxib 3 mg/kg bid at all postrandomization visits and a numerically higher response rate than naproxen 7.5 mg/kg bid at Weeks 4, 8, and 12. Improvement in each ACR Pediatric-30 core set measure was comparable to or numerically higher for celecoxib 6 mg/kg bid than naproxen or celecoxib 3 mg/kg bid. Adverse event rates were similar for all treatment groups, except that gastrointestinal adverse events were more common in the naproxen group, although the difference was not statistically significant. Celecoxib 3 mg/kg bid and 6 mg/kg bid were at least as effective as naproxen 7.5 mg/kg bid in treating the signs and symptoms of JRA over 12 weeks. All treatments were generally well tolerated.The Journal of Rheumatology 12/2008; 36(1):174-82. · 3.69 Impact Factor -
Article: Exposure-response modeling using latent variables for the efficacy of a JAK3 inhibitor administered to rheumatoid arthritis patients.
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ABSTRACT: Currently, no general methods have been developed to relate pharmacologically based models, such as indirect response models, to discrete or ordered categorical data. We propose the use of an unobservable latent variable (LV), through which indirect response models can be linked with drug exposure. The resulting indirect latent variable response model (ILVRM) is demonstrated using a case study of a JAK3 inhibitor, which was administered to patients in a rheumatoid arthritis (RA) study. The clinical endpoint for signs and symptoms in RA is the American College of Rheumatology response criterion of 20%--a binary response variable. In this case study, four exposure-response models, which have different pharmacological interpretations, were constructed and fitted using the ILVRM method. Specifically, two indirect response models, an effect compartment model, and a model which assumes instantaneous (direct) drug action were assessed and compared for their ability to predict the response data. In general, different model interpretations can influence drug inference, such as time to drug effect onset, as well as affect extrapolations of responses to untested experimental conditions, and the underlying pharmacology that operates to generate key response features does not change because the response was measured discretely. Consideration of these model interpretations can impact future study designs and ultimately provide greater insight into drug development strategies.Journal of Pharmacokinetics and Pharmacodynamics 05/2008; 35(2):139-57. · 2.06 Impact Factor -
Article: Analgesic efficacy of celecoxib in postoperative oral surgery pain: a single-dose, two-center, randomized, double-blind, active- and placebo-controlled study.
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ABSTRACT: Celecoxib 200 mg has been reported to reduce pain following dental extraction but to offer poorer pain relief than active comparators. The aim of this study was to compare the efficacy and tolerability of celecoxib 400 mg, the recommended loading dose for treatment of acute pain, with that of ibuprofen 400 mg and placebo following oral surgery. This was a single-dose, 2-center, randomized, double-blind, active- and placebo-controlled study in which patients with moderate to severe pain following third molar extraction were randomized to receive a single dose of celecoxib 400 mg, ibuprofen 400 mg, or placebo. Pain assessments were completed using a 4-point pain intensity scale where 0=no pain and 3=severe pain and a 5-point pain relief scale where 0=no pain relief and 4= complete pain relief at baseline and 18 time points over 24 hours. Primary efficacy outcome measures were time to onset of analgesia (the median time to perceptible pain relief in those patients who achieved meaningful pain relief), time-specific pain intensity difference (PID), time-specific pain relief (PR), time-specific sum of PID and PR, and time to use of rescue medication. Times to perceptible and meaningful pain relief (secondary efficacy outcome measures) were recorded using 2 stopwatches. Tolerability was assessed through recording of adverse events, clinical laboratory tests, and physical examinations (including collection of vital signs). One hundred seventy-one patients were randomized to celecoxib 400 mg (30 women and 27 men; mean [SD] age, 21.4 [4.2] years); ibuprofen 400 mg (30 women and 27 men; mean [SD] age, 22.0 [4.7] years); or placebo (34 women and 23 men; mean [SD] age, 21.6 [5.0] years). Mean times to onset of analgesia with celecoxib 400 mg and ibuprofen 400 mg were rapid and comparable (median 28 minutes and 26 minutes, respectively) and were significantly shorter than with placebo (>24 hours) (both, P<0.05 vs placebo). Compared with placebo, mean time-specific PID scores were significantly greater with celecoxib from 0.5 to 24 hours and with ibuprofen from 0.5 to 16 hours (all, P<0.05 vs placebo). Time-specific PR scores with celecoxib and ibuprofen were significantly greater from 0.75 and 0.5 hour, respectively, compared with placebo (all, P<0.05 vs placebo). PID was significantly greater with celecoxib compared with ibuprofen beginning at 11 hours (all, P<0.05). PR scores were significantly higher with celecoxib versus ibuprofen beginning at 9 hours (all, P<0.05). Median (95% CI) time to use of rescue medication with celecoxib (>24 hours) was significantly longer than with ibuprofen (10 hours, 58 minutes [8 hours, 30 minutes- 14 hours, 34 minutes]) or placebo (1 hour, 51 minutes [1 hour, 40 minutes-2 hours, 22 minutes]) (both, P<0.05). The 3 most common adverse events experienced in the celecoxib group were headache (9 [15.8%] patients), nausea (9 [15.8%] patients), and dizziness (6 [10.5%] patients). In this postsurgical dental pain study, the onset and magnitude of pain relief with celecoxib 400 mg and ibuprofen 400 mg were found to be comparable. In addition, patients who received celecoxib 400 mg as a single dose had a significantly longer time to use of rescue medication and had higher pain relief scores later in the study than those who received ibuprofen 400 mg. Celecoxib was well tolerated compared with placebo.Clinical Therapeutics 01/2007; 29 Suppl:2498-510. · 2.32 Impact Factor
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Institutions
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2010–2012
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Pfizer Inc.
New York City, NY, USA
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2011
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University of Texas Southwestern Medical Center
Dallas, TX, USA
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2009–2011
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Albany Medical College
Albany, NY, USA
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