A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens

Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a two‐fold a...

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Bibliographic Details
Published in:Clinical and translational science 2023-02, Vol.16 (2), p.258-268
Main Authors: Heijden, Lisa, Nuland, Merel, Beijnen, Jos, Huitema, Alwin, Dorlo, Thomas
Format: Article
Language:English
Subjects:
Administration, Intravenous
Anastrozole
Chromatography
Clinical Protocols
Clinical trials
Dosage
Dose-Response Relationship, Drug
Drug Development
Drug dosages
Gemcitabine
Humans
Oral administration
Pharmacokinetics
Plasma
Software
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Summary:Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a two‐fold acceptance criterion between pharmacokinetic metrics of the extrapolated microdose and the therapeutic dose. The major disadvantage of NCA is the assumption of linear extrapolation of NCA metrics. In this study, we used a naïve pooled data (NPD) modeling approach to extrapolate microdose pharmacokinetics to therapeutic pharmacokinetics. Gemcitabine and anastrozole were used as examples of intravenous and oral drugs, respectively. Data from microdose studies were used to build a parent‐metabolite model for gemcitabine and its metabolite 2′,2′‐difluorodeoxyuridine (dFdU) and a model for anastrozole. The pharmacokinetic microdose models were extrapolated to therapeutic doses. Extrapolation of the microdose showed differences in pharmacokinetic shape for gemcitabine and dFdU between the simulated and observed therapeutic concentrations, whereas the observed therapeutic concentrations for anastrozole were captured by the extrapolation. This study demonstrated the possible use and feasibility of an NPD modeling approach for the evaluation and application of microdose studies in early drug development. Last, physiologically‐based pharmacokinetic modeling might be an alternative for microdose extrapolation of drugs with complex pharmacokinetics such as gemcitabine.
ISSN:1752-8054
1752-8062
1752-8062
DOI:10.1111/cts.13446