Physiologically based pharmacokinetic modelling to investigate the impact of obesity on the pharmacokinetics of rilpivirine, efavirenz, and etravirine
Mattia Berton (1,2), Sara Bettonte (1,2), Felix Stader (3), Laurent Decosterd (4), Philip Tarr (5), Matthias Cavassini (6), Dominique Braun (7), Katharina Kusejko (7), Anna Hachfeld (8), Enos Bernasconi (9), Alexandra Calmy (10), Patrick Schmid (11), Manuel Battegay (1,2), Catia Marzolini (1,2,12)
(1) Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Switzerland, (2) University of Basel, Switzerland, (3) Certara UK Limited, United Kingdom, (4) Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, University Hospital Lausanne and University of Lausanne, Switzerland, University Department of Medicine, (5) Kantonsspital Bruderholz, University of Basel, Switzerland, (6) Service of Infectious Diseases, Lausanne University Hospital, University of Lausanne, Switzerland, (7) Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Switzerland, (8) Department of Infectious Diseases, University Hospital Bern, University of Bern, Switzerland, (9) Division of Infectious Diseases, Regional Hospital Lugano, Switzerland, (10) Division of Infectious Diseases, University Hospital Geneva, University of Geneva, Switzerland, (11) Department of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen, Switzerland, (12) Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom
Introduction: Nowadays, obesity represents a major public health problem [1]. The number of people affected by this disease is rising both in the general and HIV population [2]. Obesity is associated with several physiological changes which can reduce antiretrovirals exposure, as we previously demonstrated for bictegravir and dolutegravir [3]. Recommendations on antiretroviral dosing for obese (BMI 30-40 kg/m2) and especially for morbidly obese (BMI>40 kg/m2) are scarce in the literature. Physiologically based pharmacokinetic (PBPK) modelling is a mathematical technique that can help overcoming the limited clinical data and supporting a safe and effective drug therapy in obese.
Objectives: The objective of this study was to use PBPK modelling to investigate the pharmacokinetics of rilpivirine, efavirenz, and etravirine in obese and morbidly obese people living with HIV (PLWH) and provide dosing recommendations.
Methods: Our recently published repository describing the physiology of a White obese population [4] was implemented in the in-house PBPK model built in Matlab® [5]. The performance of our PBPK framework to predict drug disposition in obese was verified against clinical data of ten non-HIV drugs [6]. PBPK drug models for rilpivirine, efavirenz, and etravirine were previously developed and verified in young and elderly PLWH [7]. To ensure their ability to predict the pharmacokinetics in non-obese and obese, drug models were verified using clinical data from the literature and therapeutic drug monitoring (TDM) levels from the Swiss HIV Cohort Study (SHCS). Noncompartmental analysis was used to derive peak plasma concentration (Cmax), area under the curve to time t (AUCt), and trough concentration (Cτ) from the TDM data in the obese group. Models were considered verified when simulations agreed with clinical data and when the predicted vs observed pharmacokinetic parameters ratios were within the 2-fold error margin. At this point, the verified drug models were used to investigate the pharmacokinetic changes across different obesity classes (normal weight 18.5-25 kg/m2, pre-obesity 25-30 kg/m2, obesity class I 30-35 kg/m2, obesity class II 35-40 kg/m2, obesity class III 40-50 kg/m2 and above obesity class III 50-60 kg/m2).
Results: Rilpivirine, efavirenz, and etravirine simulated pharmacokinetics profiles were in agreement with the observed data and the majority of the drug levels were within the 95% normal range of the predictions. Predicted vs observed Cmax, AUCt, and Cτ ratios were 0.93, 1.05, and 0.96 in non-obese and 1, 1.23, and 0.84 in obese for rilpivirine; 1.21, 0.99, 0.94 in non-obese and 1.14 1.03, 0.92 in obese for efavirenz; and 0.93, 0.93, and 1.01 in non-obese and 1.28, 1.67, and 1.09 in obese for etravirine. All ratios were all within the 2-fold of observed clinical data demonstrating the ability of the PBPK model to predict the pharmacokinetics in both non-obese and obese. The analysis of the pharmacokinetic results in different BMI classes showed that for all three drugs there was a reduction in Cmax, AUCt and Cτ; however, this change was 25% lower only for the obesity class III and above. The simulated Cτ mean for the highest BMI group (BMI 50-60 kg/m2) were predicted to be 61, 1216, and 216 ng/mL for rilpivirine, efavirenz, and etravirine, respectively. These values are all above the clinical threshold used to define the antiviral efficacy (50, 1000, and 200 ng/mL for rilpivirine, efavirenz, and etravirine); however, the percentage of virtual individuals below the clinical threshold was higher in the morbidly obese group compared to the normal weight group (45% vs 4% for rilpivirine, 29% vs 9% for efavirenz, and 45% vs 5% for etravirine).
Conclusions: This study is the first one to compare rilpivirine, efavirenz, and etravirine full pharmacokinetic profiles between non-obese and obese PLWH. It demonstrates that our PBPK model can reproduce clinical observed data in both studied populations. In addition, the pharmacokinetic analysis across BMI groups shows that obesity lowers the exposure of three evaluated drugs especially in individuals with BMI > 40 kg/m2. Nonetheless, Cτ mean levels were still above the clinical efficacy target concentration also in the highest BMI group. However, a greater proportion of virtual morbidly obese individuals had Cτ concentrations below the clinical threshold compared to the normal weight group, therefore TDM is advised in morbidly obese individuals.
References:
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