Population pharmacokinetics of rilpivirine following oral administration and long-acting intramuscular injection in real-world people with HIV

Paul Thoueille; Susana Alves Saldanha; Fabian Schaller; Eva Choong; François Veuve; Aline Munting; Matthias Cavassini; Dominique Braun; Huldrych F Günthard; Jessy J Duran Ramirez; Bernard Surial; Hansjakob Furrer; Andri Rauch; Pilar Ustero; Alexandra Calmy; Marcel Stöckle; Caroline Di Benedetto; Enos Bernasconi; Patrick Schmid; Catia Marzolini; François R Girardin; Thierry Buclin; Laurent A Decosterd; Monia Guidi

doi:10.3389/fphar.2024.1437400

Population pharmacokinetics of rilpivirine following oral administration and long-acting intramuscular injection in real-world people with HIV

Front Pharmacol. 2024 Nov 15:15:1437400. doi: 10.3389/fphar.2024.1437400. eCollection 2024.

Authors

Paul Thoueille^{1

2}, Susana Alves Saldanha², Fabian Schaller², Eva Choong², François Veuve², Aline Munting³, Matthias Cavassini³, Dominique Braun^{4

5}, Huldrych F Günthard^{4

5}, Jessy J Duran Ramirez^{4

5}, Bernard Surial⁶, Hansjakob Furrer⁶, Andri Rauch⁶, Pilar Ustero⁷, Alexandra Calmy^{7

8}, Marcel Stöckle⁹, Caroline Di Benedetto¹⁰, Enos Bernasconi¹¹, Patrick Schmid¹², Catia Marzolini^{2

9

13}, François R Girardin^{1

2}, Thierry Buclin¹, Laurent A Decosterd², Monia Guidi^{1

14

15}

Affiliations

¹ Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
² Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
³ Service of Infectious Diseases, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
⁵ Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
⁶ Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁷ Division of Infectious Diseases, Geneva University Hospitals, Faculty of Medicine, Geneva, Switzerland.
⁸ Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland.
¹⁰ Division of Infectious Diseases, Ente Ospedaliero Cantonale, Lugano, Switzerland.
¹¹ Division of Infectious diseases, Ente Ospedaliero Cantonale, University of Geneva, and University of Southern Switzerland, Lugano, Switzerland.
¹² Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
¹³ Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
¹⁴ Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁵ Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland.

Abstract

Background: The pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations.

Aims and methods: Our population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively).

Results: Rilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (C_trough) compared to males, which was not considered to be clinically relevant.

Conclusion: Overall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine C_trough would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of C_trough would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL).

Keywords: HIV; NONMEM; long-acting injectable; population pharmacokinetics; rilpivirine.

Copyright © 2024 Thoueille, Saldanha, Schaller, Choong, Veuve, Munting, Cavassini, Braun, Günthard, Duran Ramirez, Surial, Furrer, Rauch, Ustero, Calmy, Stöckle, Di Benedetto, Bernasconi, Schmid, Marzolini, Girardin, Buclin, Decosterd and Guidi.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This independent work was funded by the Swiss National Science Foundation, grant number N^◦ 324730_192449. This study was performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #201369), by SHCS project #879, and by the SHCS research foundation. The public funding source of the study had no role in the design of the study, in data collection, analysis, and interpretation, in manuscript writing, or in the decision to submit the article for publication. This study received no support from pharmaceutical industries.