A novel workflow integrating whole-body PET microdosing data and therapeutic-dose pharmacokinetics across species to inform first-in-human dose selection

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.