Rob ter Heine’s research while affiliated with Radboud University Medical Centre (Radboudumc) and other places

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Publications (218)


Fig 4 Final structural model of olaparib
Fig. 5 Stratified prediction-corrected visual predictive check of the final olaparib model stratified per treatment. Y-axis represents olaparib concentrations. The observations are indicated by the circles. The median (continuous line) and 12.5th and 87.5th percentiles (dashed
Population Pharmacokinetics of Cobicistat and its Effect on the Pharmacokinetics of the Anticancer Drug Olaparib
  • Article
  • Full-text available

February 2025

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4 Reads

Clinical Pharmacokinetics

Joanneke K. Overbeek

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Rob ter Heine

Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib. Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling. Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat. The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose. NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).

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Characteristics of PBPK model simulations
Model-informed repurposing of eliglustat for treatment and prophylaxis of Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) in children

February 2025

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18 Reads

Pediatric Nephrology

Background Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) is a severe illness predominantly affecting young children, with limited treatment options beyond supportive care. Eliglustat, approved for Gaucher disease, shows potential in reducing Shiga toxin binding to target glomerular endothelial cells in vitro, prompting interest as a treatment for STEC-HUS. However, it remains unknown what dose is likely to be effective and safe for treatment of STEC-HUS in the pediatric population. We hypothesize that effective and safe levels of eliglustat can be reached in children. Methods We identified pharmacokinetic targets of efficacy for treatment and prophylaxis of STEC-HUS based on a preclinical model and human cardiac safety data. Then, we developed oral and intravenous dosing regimens using population pharmacokinetic (popPK) simulations based on an existing model enriched to allow extrapolation to a simulated virtual pediatric population. These dosing regimens were then confirmed using a verified physiologically based pharmacokinetic (PBPK) model. Results We simulated, using popPK data, oral and intravenous dosing regimens resulting in adequate target exposure in > 90% of all patients, with minimal expected risk for cardiotoxicity. Confirmation of these dosing regimens with PBPK modeling resulted in very similar exposure, with lower interindividual variability and minimal toxicity potential. Conclusions Based on pharmacokinetic modeling, we developed oral and intravenous eliglustat dosing regimens that are likely safe and effective for treatment of STEC-HUS and prophylaxis in case of outbreaks of STEC infections. Clinical evaluation of these dosing regimens in children suspected of or diagnosed with STEC-HUS is required and should include assessment of pharmacokinetics, efficacy, and safety (e.g., ECG monitoring). Graphical abstract


Very Early Health Technology Assessment for Potential Predictive Biomarkers in the Treatment of Advanced Non-Small Cell Lung Cancer

January 2025

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13 Reads

PharmacoEconomics - Open

Immune checkpoint inhibitor (ICI)-containing treatment is currently prescribed as first-line treatment for all patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, only 30–45% of patients show no progression within 12 months after treatment start. Various biomarkers are being studied to save costly and potentially harmful treatment in non-responders. We evaluated the cost-effectiveness of implementing a hypothetical predictive biomarker for ICI-containing treatment response compared with standard of care (e.g., no implemented biomarker) for pembrolizumab-containing treatment in patients with advanced NSCLC in the Netherlands. Standard-of-care-based and predictive-biomarker-based strategies were compared using Markov models for three first-line pembrolizumab-containing treatments depending on a patient’s tumor programmed cell death ligand-1 (PD-L1) expression and histology. A Dutch healthcare system perspective was adopted. Assuming a receiver operating characteristic-area under the curve of 1.0 in identifying responders, alternative treatments were offered for non-responders in the predictive-biomarker-based strategy. Parameters and assumptions were based on real-world data from surveys, literature using a targeted search, expert opinion, and registries. Outcomes included differences in costs, survival (life years (LYs)), and survival corrected for health-related quality of life (QoL) quality-adjusted life-years (QALYs) between the predictive-biomarker- and standard-of-care-based strategy. Implementing a predictive biomarker in pembrolizumab-carboplatin-paclitaxel treatment led to a mean survival reduction of 24 days (− 0.067 LYs) (18 days corrected for QoL (− 0.049 QALYs)), with cost savings of €22,606 compared with standard of care. Pembrolizumab monotherapy and pembrolizumab-pemetrexed-platinum treatments showed survival reductions of 4.5 and 3.9 months, respectively (3.6 and 2.8 months corrected for QoL), with cost savings of €24,345 and €28,456. Sensitivity analyses confirmed consistent cost savings and survival reductions. Survival losses were mainly observed due to the lower survival rates associated with the alternative first-line treatment options available for non-responders in the predictive-biomarker-based strategy within each pembrolizumab-containing treatment regimen. Pembrolizumab-carboplatin-paclitaxel treatment also showed survival gains under certain conditions related to QoL and survival estimates. Our study highlights the importance of careful de-implementation of ICI-treatments in advanced NSCLC, balancing costs reductions and side effects without comprising survival. In the pembrolizumab-carboplatin-paclitaxel treatment regimen, the survival loss could be considered negligible. Future research should define acceptable tradeoffs and thresholds for de-implementation, considering factors such as survival of alternative treatments and responder classification to guide predictive biomarker implementation and optimize health resource allocation.



Figure 1 | Classification of thrombotic microangiopathies (TMAs). 1 ary, primary; AAV, anti-neutrophil cytoplasmic antibody-associated vasculitis; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ACTN4, actinin 4; aHUS, atypical hemolytic uremic syndrome; C3G, C3 glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; EXOSC3, exosome component 3; DGKE, gene encoding diacylglycerol kinase 3; FH, factor H; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; HIV, human immunodeficiency virus; HUS, hemolytic uremic syndrome; HSD11B2, 1-beta-hydroxysteroid dehydrogenase; IgAN, IgA nephropathy; INF2, inverted formin 2; MMACHC, methylmalonic aciduria and homocystinuria cblC type; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTR, 5-methyltetrahydrofolate homocysteine S-methyltransferase; NPHS2, podocin; SLE, systemic lupus erythematosus; SRC, scleroderma renal crisis; STEC, Shiga toxin-producing Escherichia coli; TTP, thrombotic thrombocytopenic purpura; TSEN2, transfer RNA splicing endonuclease subunit 2. Modified with permission from Wong E, Maville C, Allen G, et al. The Annual Report of the National Renal Complement Therapeutics Centre 2021/22. National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals National Health Service Foundation Trust; 2022. 2 To optimize viewing of this image, please see the online version of this article at www.kidney-international.org.
Complement biomarker utility in TMAs
Predictors of eculizumab response: multivariate analysis of the factors associated with eGFR > 60 ml/min per 1.73 m 2 at 6 mo after commencing eculizumab 6
Outcomes from the International Society of Nephrology Hemolytic Uremic Syndromes International Forum

January 2025

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92 Reads

Hemolytic uremic syndromes (HUSs) are a heterogeneous group of conditions, only some of which are mediated by complement (complement-mediated HUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included the nomenclature of HUS, novel complement testing strategies, identification of biomarkers, genetic predisposition to atypical HUS, optimal dosing and withdrawal strategies for C5 inhibitors, treatment of kidney transplant recipients, disparity of access to treatment, and the next generation of complement inhibitors in complement-mediated HUS. The current rationale for optimal patient management is described.




Fig. 2. Sagittal and axial images from the MRI of thoracolumbar spine at the 3-week follow-up (contrastenhanced T1-weighted sequence without fat suppression), showing resolution of the previous contrastenhancement. The axial image is at the level of the L2 vertebral body.
Polyradiculitis as a Neurological Complication Associated with Adagrasib: A Case Report

November 2024

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14 Reads

Case Reports in Oncology

Introduction: Adagrasib is an upcoming anticancer treatment for KRAS G12C-mutated non-small-cell lung carcinoma, colorectal cancer and potentially other solid tumors harboring this mutation. It is generally well-tolerated and reports of neurological adverse events so far have been limited. Case Presentation: We present to our best knowledge the first case of a 70-year-old woman who was admitted with polyradiculitis as a treatment-related complication of adagrasib. Symptoms resolved after treatment with prednisone and therapy interruption of adagrasib followed by a permanent dose reduction. After the dose reduction, there was an ongoing effective tumor response at follow-up, and serum concentrations of adagrasib remained within the therapeutic index. Conclusion: Through this case report, we aim to bring attention to the possibility of this side effect, as we believe it is important to be aware of it for future patients undergoing treatment with adagrasib.


CONSORT diagram: trial flow
Boxplot of reductions in CRP in randomised trial arms
Comparison of pharmacokinetic parameters from conventional and allometric dosing regimens. Achieved exposure, reported as AUC0-24 h on the third day of treatment, using different dosing regimens. The red dashed line indicates the mean exposure level of 3.45 mg*h/L in adults, that is used as a reference (25). The solid dots indicate the mean AUC0-24 h resulting from the simulation. The boxes represent the predicted interquartile range and the solid black line represents the predicted median. The whiskers depict the extremes. A 10 mg/kg body weight; B 15 mg/kg body weight; C 20 mg/kg body weight; D allometric dosing, consisting of a flat dose per weight band according to Table 5. This dosing scheme results in a consistent exposure across all weight bands
Azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a phase II randomised controlled trial

November 2024

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17 Reads

BMC Medicine

Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection. Methods We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled. Results Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls. Conclusions We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection. Trial registration ISRCTN49726849 (registered on 27th October 2017).


True clearance versus predicted clearance for all covariate models. Each dot represents an individual. The line represents the line of unity
A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed

October 2024

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19 Reads

Cancer Chemotherapy and Pharmacology

Introduction For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. Methods We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the “true” values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. Results The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. Conclusions In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.


Citations (62)


... Studies have highlighted the frequency of co-prescriptions that may lead to harmful interactions, particularly with medications that influence metabolic pathways such as CYP3A4 and P-glycoprotein (Stöllberger et al., 2023;Shurrab et al., 2022). Identifying these interactions is essential for clinicians to make informed decisions regarding anticoagulant therapy, ensuring that patients receive appropriate and effective treatment while minimizing the risk of bleeding and other adverse events (Gulikers et al., 2024). ...

Reference:

MANAGEMENT OF ANTICOAGULATION IN ATRIAL FIBRILLATION: MINIMIZING DRUG INTERACTIONS WITH DOACS
Proactive monitoring of drug-drug interactions between direct oral anticoagulants and small-molecule inhibitors in patients with non-small cell lung cancer

British Journal of Cancer

... Fortunately, a number of promising new antimalarial agents are progressing through the development pipeline [3], and the ability to test the transmission blocking activity of these novel agents will be essential for informing partner drug selection and optimal use of these agents. The transmission blocking activity of antimalarial agents has been assessed in Phase 2/3 studies, generating direct evidence of effectiveness against naturally acquired infections in endemic settings [4,5,6,7,8]. However, this approach is associated with significant challenges, including the confounding effects of adjunctive curative therapy, pre-existing immunity in participants [9], variation in mosquito infectivity [10], as well as logistical, infrastructure and regulatory considerations [11]. ...

Artemether–lumefantrine with or without single-dose primaquine and sulfadoxine–pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali
  • Citing Article
  • May 2024

The Lancet Microbe

... Furthermore, cost-benefit analyses are warranted, including costs for the MIPD software and workload, the benefit of enabling AUC-guided dosing for vancomycin specifically, as well as the potential to broaden the application to additional drugs. There is a current research focus on developing and applying models for MIPD purposes within a range of therapeutic areas, e.g., oncology, antifungal and immunosuppressive therapy [40][41][42][43] as well as novel machine learning approaches [44,45], and the results of this study can be used to facilitate implementation of these advances in clinical practice. Finally, MIPD expertise within health care is needed for extension to other institutions. ...

Personalized Antifungal Therapy Through Model-Informed Precision Dosing of Posaconazole

Clinical Pharmacokinetics

... The area under the curve (AUC) and peak plasma concentration (Cmax) showed dose-dependent behavior. A manuscript providing pharmacokinetic data on ibogaine was recently published (Knuijver et al., 2024). However, data should be interpreted cautiously because subjects were administered with metoclopramide, a CYP2D6 inhibitor, before ibogaine administration. ...

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients

Journal of Psychopharmacology

... A study investigating these components is under way and will help us understand these management strategies for patients with agitation. 200 Predictive tools have been proposed to identify patients who could be at greater risk of problems after leaving the ICU. 201 Although studies are needed to determine how these tools might affect patients, they could potentially evolve to include ICU sedation and pain management variables known to affect outcomes. ...

A multicomponent intervention program to Prevent and Reduce AgItation and phySical rEstraint use in the ICU (PRAISE): study protocol for a multicenter, stepped-wedge, cluster randomized controlled trial

Trials

... This is supported by our retrospective results and currently tested prospectively in several trials that either lower the dose or extend the dosing interval (NCT04032418 and NCT04295863). [36][37][38][39][40] This study has three important limitations inherent to the retrospective, observational design. First, a proportion of patients in both cohorts were not fully treated according to dosing scheme of the allocated cohort. ...

Integrating treatment cost reduction strategies and biomarker research to reduce costs and personalize expensive treatments: an example of a self-funding trial in non-small cell lung cancer

... Samples were promptly refrigerated and centrifuged at 2500 × g for 10 min before 2 mL of supernatant was preserved at -20 °C for subsequent analysis. Teicoplanin concentrations were determined using liquid chromatography-tandem mass spectrometry [20][21][22]. The linear range of the method was 1.0-100.0 ...

Development and validation of a bioanalytical assay for the measurement of total and unbound teicoplanin in human serum

Journal of Antimicrobial Chemotherapy

... Currently in (hospital) pharmacies, drug formulations are compounded by using manual capsule filling machines or by manipulating existing dosage forms. Both approaches come with safety and quality concerns as these practices may lead to dosing errors, putting patients at risk [6][7][8][9]. In contrast, studies on 3DP have demonstrated the feasibility of printing personalized medication with varying dose ranges and with high quality [10,11]. ...

Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube
  • Citing Article
  • October 2023

Journal of Antimicrobial Chemotherapy

... Although some evidence suggests that ISA is not readily eliminated through dialysis [173], a study involving 22 critically-ill patients showed a 42% reduction in ISA concentration post dialysis [174]. Recently, Jansen et al. proposed that previous findings from pharmacokinetic and pharmacodynamic research on isavuconazole, which assume a constant protein binding, should be reconsidered to investigate such variabilities [175]. In ECMO patients, a stepwise approach aided by real-life TDM has shown that a 400 mg loading dose of isavuconazole is suitable to achieve rapid median plasma concentrations of ≥1 mg/L without reaching a toxic range [176,177]. ...

High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints

Clinical Pharmacokinetics

... There are a limited number of studies on isavuconazole in critically ill patients, but dosing adjustments [65,66] and higher loading doses have been recommended. No associations between patient characteristics and endpoints were found in this study, likely due to the small number of patients administered isavuconazole. ...

Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies

Clinical Pharmacokinetics