Prevalence and Risk Factors of poor oral bioavailability in preclinical pharmacokinetic models

Feng Yang; L. Wang; W. Chen

doi:10.5281/zenodo.22813136

Authors

Feng Yang Department of Pharmaceutical Sciences, Fraser Institute of Drug Delivery Research Author https://orcid.org/2251-9578-9000-4330
L. Wang Department of Pharmaceutical Sciences, Lena Research Center for Pharmaceutical Sciences Author https://orcid.org/4459-8267-0445-7138
W. Chen Division of Pharmaceutical Sciences, Dnieper Institute for Advanced Pharmaceutical Sciences Author https://orcid.org/3247-9539-8354-4027

DOI:

https://doi.org/10.5281/zenodo.22813136

Keywords:

oral bioavailability, preclinical pharmacokinetics, biopharmaceutics classification, first-pass metabolism, P-glycoprotein

Abstract

Graphical abstract

Background: Poor oral bioavailability is a leading cause of candidate attrition in preclinical drug discovery, arising from physicochemical, metabolic, and transporter-mediated determinants of absorption [3,9].

Objective: This review synthesizes the preclinical pharmacokinetic literature on the prevalence of poor oral bioavailability across compound classes and its principal risk factors.

Methods: We reviewed peer-reviewed preclinical pharmacokinetic studies and industry-wide attrition analyses reporting oral bioavailability alongside physicochemical or biopharmaceutic descriptors, drawn from rodent, canine, and primate screening cascades.

Findings: Reported prevalence of low oral bioavailability ranges from roughly one-quarter of small-molecule candidates to over two-thirds of peptide candidates [10,12]; low solubility/permeability [3], high first-pass extraction [24], and P-glycoprotein efflux [27] are the most consistent, often compounding risk factors, modulated by species and formulation [5,31].

Conclusions: Integrated early screening across physicochemical, metabolic, and transporter domains, interpreted with speciesand formulation-awareness, offers the most reliable route to derisking oral exposure [24,27].

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