External Evaluation of Population Pharmacokinetic Models of Cabotegravir, During Its Oral and Intramuscular Administration in <scp>HIV</scp> ‐Infected Patients

Cabotegravir (CAB), combined with rilpivirine, is the first long-acting injectable therapy approved for HIV-1 maintenance treatment. While adherence and patient satisfaction have been improved, pharmacokinetic (PK) variability remains a concern. Two population PK models have been developed: one based on data from phase I-III trials and the other on routine clinical data. However, neither model has undergone thorough external evaluation. The aim of this study was to evaluate the predictive performance of these models using an independent prospective dataset to evaluate their suitability to support model-informed precision dosing (MIPD). External validation was performed using data from the French observational and multicenter (n = 14) ANRS0255 CARLAPOP study (736 HIV-infected patients, representing 2192 concentrations). Models were implemented using MONOLIX software and evaluated using goodness-of-fit, prediction-based, and simulation-based diagnostics. For Han's model, regarding plasma concentrations following intramuscular administration, Median Prediction Error (MDPE) was -1.2% (PRED) and -4.4% (IPRED); Median Absolute Prediction Error (MDAPE) was 36.6% (PRED) and 17.9% (IPRED). For Thoueille's model, MDPE was -24.2% (PRED) and -9.2% (IPRED); MDAPE was 39.0% (PRED) and 15.3% (IPRED). However, < 70% of predictions were within a 20% error margin with both models. Graphical analyses of Thoueille's model showed systemic bias, particularly in women, nonsmokers, and patients with higher body mass index. Therefore, neither model was considered reliable enough for MIPD application in our population. Although Han et al.'s model demonstrated higher predictive performances, further improvements are required before it can be reliably applied for MIPD in daily routine.

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Journal
CPT Pharmacometrics & Systems Pharmacology
Published
2026-05-22
DOI
https://doi.org/10.1002/psp4.70180
Primary Topic
HIV/AIDS drug development and treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

External Evaluation of Population Pharmacokinetic Models of Cabotegravir, During Its Oral and Intramuscular Administration in HIV ‐Infected Patients

Stéphane Bouchet, François Parant, Alexandre Destère, Patrice Muret et al.
CPT Pharmacometrics & Systems Pharmacology
HIV/AIDS drug development and treatment
article

External Evaluation of Population Pharmacokinetic Models of Cabotegravir, During Its Oral and Intramuscular Administration in HIV ‐Infected Patients

Stéphane Bouchet, François Parant, Alexandre Destère, Patrice Muret, Sébastien Lalanne, Sihem Benaboud, Jennifer Lagoutte‐Renosi, Nicolas Venisse, Matthieu Grégoire, Caroline Solas, Peggy Gandia, Quentin Renou, the CARLA Study Group, Minh P. Lê, Gilles Peytavin, Nadège Néant, Florian Lemaitre
article en

Abstract

Cabotegravir (CAB), combined with rilpivirine, is the first long-acting injectable therapy approved for HIV-1 maintenance treatment. While adherence and patient satisfaction have been improved, pharmacokinetic (PK) variability remains a concern. Two population PK models have been developed: one based on data from phase I-III trials and the other on routine clinical data. However, neither model has undergone thorough external evaluation. The aim of this study was to evaluate the predictive performance of these models using an independent prospective dataset to evaluate their suitability to support model-informed precision dosing (MIPD). External validation was performed using data from the French observational and multicenter (n = 14) ANRS0255 CARLAPOP study (736 HIV-infected patients, representing 2192 concentrations). Models were implemented using MONOLIX software and evaluated using goodness-of-fit, prediction-based, and simulation-based diagnostics. For Han's model, regarding plasma concentrations following intramuscular administration, Median Prediction Error (MDPE) was -1.2% (PRED) and -4.4% (IPRED); Median Absolute Prediction Error (MDAPE) was 36.6% (PRED) and 17.9% (IPRED). For Thoueille's model, MDPE was -24.2% (PRED) and -9.2% (IPRED); MDAPE was 39.0% (PRED) and 15.3% (IPRED). However, < 70% of predictions were within a 20% error margin with both models. Graphical analyses of Thoueille's model showed systemic bias, particularly in women, nonsmokers, and patients with higher body mass index. Therefore, neither model was considered reliable enough for MIPD application in our population. Although Han et al.'s model demonstrated higher predictive performances, further improvements are required before it can be reliably applied for MIPD in daily routine.

CPT Pharmacometrics & Systems PharmacologyVol. 15(6)
Délégation Paris 5 (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), École des Hautes Études en Santé Publique (FR), École Nationale Vétérinaire de Toulouse (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Paris Cité (FR), Aix-Marseille Université (FR), Centre Hospitalier Universitaire de Nice (FR), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Toulouse (FR), Université de Poitiers (FR), Centre Hospitalier Universitaire de Besançon (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Sorbonne Paris Cité (FR), Hôpital Cochin (FR), Hospices Civils de Lyon (FR), Institut de Recherche en Santé, Environnement et Travail (FR), Centre Hospitalier Universitaire de Poitiers (FR), Hôpital Pellegrin (FR), Laboratoire Jean-Alexandre Dieudonné (FR), Hôpital Lyon Sud (FR), Centre d'Investigation Clinique de Nantes (FR), Pharmacochimie et Biologie pour le Développement (FR), Hôpital Bichat-Claude-Bernard (FR), Centre Hospitalier Universitaire de Rennes (FR), Hôpital de la Timone (FR), Institut de Recherche pour le Développement (FR), Cibles et Médicaments des Infections et de l'Immunité, Université de Rennes (FR), Nantes Université (FR)
Agence Nationale de Recherches sur le Sida et les Hépatites Virales
Good health and well-being
Openalex Percentile: Top 7%
HIV/AIDS drug development and treatment
DOIOpen Access PDFOpenAlex
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