A novel workflow integrating whole-body PET microdosing data and therapeutic-dose pharmacokinetics across species to inform first-in-human dose selection
- 1Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en sante, environnement et travail) - UMR_S 1085, Rennes; Universite Paris Cite and Universite Sorbonne
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.
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BibTeX
@misc{nguyen2026novel,
title = {{A novel workflow integrating whole-body PET microdosing data and therapeutic-dose pharmacokinetics across species to inform first-in-human dose selection}},
author = {B. T. Nguyen and A. Barrail-Tran and M. Ursino and S. Goutal and F. Caille and T. Naninck and R. Le Grand and O. Lambotte and N. Tournier and E. Comets},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.748870},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.748870v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - A novel workflow integrating whole-body PET microdosing data and therapeutic-dose pharmacokinetics across species to inform first-in-human dose selection
AU - B. T. Nguyen
AU - A. Barrail-Tran
AU - M. Ursino
AU - S. Goutal
AU - F. Caille
AU - T. Naninck
AU - R. Le Grand
AU - O. Lambotte
AU - N. Tournier
AU - E. Comets
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.748870
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.748870v1
AB - 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.
ER -