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.…
First-in-human clinical trials necessitate dose extrapolation from animal pharmacokinetic studies, complemented by safety evaluations. Subtherapeutic doses of radiolabeled compounds can be employed in preclinical and initial clinical phases to acquire dynamic pharmacokinetic insights, which could subsequently guide pharmacologically-based pharmacokinetics (PBPK) models via whole-body PET data.
The objectives included creating a PET-informed modelling framework for extrapolation from preclinical to human levels, using dolutegravir as a case study. The methodological approach involved developing a structured workflow that merged micro- and conventional-dose data for interspecies and dose extrapolation. A whole-body PBPK model was constructed in PK-Sim/MoBi (version 12.1) utilizing non-human primate (NHP) data across five major organs, incorporating dolutegravir's physico-chemical properties, protein binding, metabolism, and efflux mechanisms.
Sensitivity analyses and parameter estimation were carried out sequentially, first with PET microdosing organ data over a three-hour period, followed by fluid and tissue concentrations resulting from a 2.5 mg/kg intravenous injection. Ultimately, 100 Caucasian healthy adults (50% male, aged 20-80 years) receiving 50 mg orally after high-fat meals were simulated using two distinct sets of estimated parameters.
The results demonstrated that dolutegravir blood data were effectively represented in NHPs over a three-hour timeframe, with parameters adjusted to account for macrodose-related changes. However, microdose-based parameter estimates consistently underestimated exposure, although integrating NHP micro- and conventional dose data allowed for accurate predictions of steady-state geometric mean AUC0-24 and Cmax, closely mirroring human-reported profiles, albeit slightly underestimating Ctrough.
In conclusion, the implementation of PET-PBPK modelling, which combines micro- and conventional doses in NHPs, effectively predicted dolutegravir concentrations in healthy volunteers. This approach also enhanced tissue distribution insights. This proof-of-concept study indicates that early acquisition of PET data can contribute to robust priors for first-in-human clinical trials.
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