A novel workflow integrating whole-body PET microdosing data and therapeutic-dose pharmacokinetics across species to inform first-in-human dose selection
Year: 2026
Type: preprint
Abstract: Introduction First-in-human studies require dose extrapolation from pharmacokinetic animal studies combined with safety assessments. Subtherapeutic doses of radiolabelled drugs can be administered in preclinical and early clinical development to gain a dynamic pharmacokinetic understanding, potentially informing pharmacologically-based pharmacokinetics (PBPK) models through whole-body PET data. Aims to develop a PET-informed modelling framework for preclinical-to-human extrapolation, with dolutegravir as a case-study. Methods We developed a structured workflow integrating micro- and conventional-dose data for interspecies and dose extrapolation. We built a whole-body PBPK model in PK-Sim/MoBi (v12.1) using non-human primate (NHP) data in 5 key organs incorporating dolutegravir physico-chemical properties, protein binding, metabolism and efflux. Sensitivity analyses and parameter estimation were performed sequentially first with PET microdosing organ data over 3h, then with fluid and tissue concentrations following a 2.5 mg/kg IV injection. Finally, 100 Caucasian healthy adults (50% male, 20–80 years) receiving 50 mg qd po after high-fat meals were simulated using the two sets of estimated parameters and physiology-related parameter distributions provided by PK-Sim. Results Dolutegravir blood data were well described in NHPs over 3 hours, with parameters adjusted to handle the macrodose-related changes. While microdose-based parameter estimates systematically underpredicted exposure, combining NHP micro- and conventional dose data predicted steady-state geometric mean AUC 0-24 and C max closely matching human reported profiles, although slightly underpredicting C trough . Conclusions PET-PBPK modelling combining micro- and conventional doses in NHPs successfully predicted dolutegravir concentrations in healthy volunteers, additionally informing tissue distribution. This proof-of-concept study supports early PET data acquisition to build robust priors for first-in-human studies. Key Points This study presents the first integration of PET microdosing data from nonhuman primates into a whole- body physiologically based pharmacokinetic model, enabling quantitative extrapolation of dolutegravir pharmacokinetics to humans. The developed model using PET data and further calibrated using traditional plasma concentration profiles in nonhuman primates was able to predict human steady-state plasma exposure metrics (C max , AUC 0-24h , half-life) in human. PET-informed modelling provides dynamic organ-specific tissue distribution, offering novel insights into drug disposition not feasible with conventional preclinical methods. This workflow holds clinical relevance by complementing phase I studies for refined first-in-human dose selection and early tissue exposure assessment, potentially accelerating safer drug development and limiting animal experiments.
Institutions: Inserm, École des Hautes Études en Santé Publique, Université Paris Cité, Université Sorbonne Paris Nord, Institut de Recherche en Santé, Environnement et Travail, Infection, Anti-microbiens, Modélisation, Evolution, Université de Rennes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, CEA Paris-Saclay - Etablissement de Fontenay-aux-roses, Assistance Publique – Hôpitaux de Paris, Infectious Disease Models and Innovative Therapies, Bicêtre Hospital, Institut national de recherche en sciences et technologies du numérique, Heka : Méthodes basées sur les données et modèles en santé pour l'acquisition de connaissances, Centre National de la Recherche Scientifique, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212086304