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Population Pharmacokinetic Analysis of Doravirine in Real-World People with HIV
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  • Paul Thoueille,
  • Luc Delarive,
  • Matthias Cavassini,
  • Thierry Buclin,
  • Laurent Decosterd,
  • Catia Marzolini,
  • François Girardin,
  • Monia Guidi
Paul Thoueille
Lausanne University Hospital
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Luc Delarive
Lausanne University Hospital
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Matthias Cavassini
Lausanne University Hospital
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Thierry Buclin
Lausanne University Hospital
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Laurent Decosterd
Lausanne University Hospital
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Catia Marzolini
Lausanne University Hospital
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François Girardin
Lausanne University Hospital
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Monia Guidi
Lausanne University Hospital

Corresponding Author:[email protected]

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Abstract

Aim: The pharmacokinetics of doravirine have been studied in clinical trials, but not in real-world settings. Our study aims to characterize and identify factors influencing doravirine pharmacokinetics (a CYP3A4 substrate) in real-world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one-compartment model with first-order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 reduced CL by 50%, and a 30% decrease in CL was observed in an 80-year-old compared to a 55-year-old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between-subject variability in CL. Model-based simulations predicted 2.8-fold and 1.6-fold increases in median steady-state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co-administered. Conclusion: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected non-adherence or pregnancy.
20 Oct 2023Submitted to British Journal of Clinical Pharmacology
20 Oct 2023Submission Checks Completed
20 Oct 2023Assigned to Editor
20 Oct 2023Review(s) Completed, Editorial Evaluation Pending
23 Oct 2023Reviewer(s) Assigned
12 Nov 2023Editorial Decision: Revise Major
14 Nov 20231st Revision Received
14 Nov 2023Submission Checks Completed
14 Nov 2023Assigned to Editor
14 Nov 2023Review(s) Completed, Editorial Evaluation Pending
18 Nov 2023Editorial Decision: Accept