Estimating the variability in fraction absorbed as a paradigm for informing formulation development in early clinical drug development

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Abstract

Purpose:

Inter-subject variability in oral drug absorption is usually reported using bioavailability, which has the components: fraction absorbed (fa), fraction passing the gut wall (fg) and fraction escaping hepatic metabolism (fh). In this study, we sought to separate the absorption (fa * fg) and elimination (fh) components of bioavailability to study variability of absorption and to investigate the effect of formulations, gastric pH and food on absorption variability.

Methods:

Four compounds from the AstraZeneca database with a range of reported bioavailabilities (high, intermediate 1&2 and low) were selected. First, a disposition model using intravenous data was developed; Second, intrinsic clearance and hence hepatic extraction ratio was estimated based on the “well stirred” model; lastly, the oral data were included to enable estimation of fa * fg as a separate component to hepatic extraction. Population pharmacokinetic model fitting was undertaken with NONMEM v.7.2.

Results:

The limiting step in absorption for intermediate 1 was dissolution rate and fa * fg variability increased under elevated gastric pH (15% vs. 38%, respectively). Absorption of solution formulation intermediate 2 increased by 17% in the presence of food but the prolonged release formulation's absorption didn't differ under fasted or fed state. Variability wasn't affected by food for both formulations (˜ 30%). For the low bioavailable compound, variability decreased when formulated as a prolonged-release formulation (39% vs. 15%).

Conclusions:

The method described here enables an exploration of drug absorption inter-subject variability using population pharmacokinetics. Implementation of such an approach may aid the formulation design process through a better understanding of the factors affecting oral drug absorption variability.

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