Affiliation:
1. Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research University Hospital Basel Basel Switzerland
2. Faculty of Medicine University of Basel Basel Switzerland
3. Certara UK Limited Sheffield UK
4. Department of Molecular and Clinical Pharmacology University of Liverpool Liverpool UK
Abstract
AbstractAimsIntramuscular cabotegravir/rilpivirine (IM CAB/RPV) are metabolized by UGT1A1/CYP3A4. Efavirenz induces both enzymes; therefore, switching from an efavirenz‐containing regimen to IM CAB/RPV could possibly result in suboptimal levels. Due to their long dosing interval, clinical studies with IM CAB/RPV are challenging. We used physiologically based pharmacokinetics (PBPK) modelling to simulate the switch from efavirenz to IM CAB/RPV.MethodsFirst, we developed the drug models and verified the performance of the PBPK model to predict the pharmacokinetics of IM cabotegravir, IM rilpivirine and efavirenz by comparing the simulations against observed clinical data. Second, we verified the ability of the model to predict the effect of residual induction with observed data for the switch from efavirenz to dolutegravir or rilpivirine. Finally, we generated a cohort of 100 virtual individuals (20–50 years, 50% female, 18.5–30 kg/m2) to simulate IM CAB/RPV concentrations after discontinuing efavirenz in extensive and slow metabolizers of efavirenz.ResultsIM CAB concentrations were predicted to decrease by 11% (95% confidence interval 7–15%), 13% (6–21%) and 8% (0–18%) at day 1, 7 and 14 after efavirenz discontinuation. CAB concentrations were predicted to remain above the minimal efficacy threshold (i.e., 664 ng/mL) throughout the switch period both in extensive and slow metabolizers of efavirenz. Similarly, IM RPV concentrations were modestly decreased with the lowest reduction being 10% (6–14%) on day 7 post last efavirenz dose.ConclusionOur simulations indicate that switching from an efavirenz‐containing regimen to IM CAB/RPV does not put at risk of having a time window with suboptimal drug levels.
Funder
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Subject
Pharmacology (medical),Pharmacology
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