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

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• 作者：Sarit Cohen Rabbie^a ; ^{sarit.rabbie@astrazeneca.com" class="auth_mail" title="E-mail the corresponding author} ; Paul D. Martin^b ; Talia Flanagan^b ; Abdul W. Basit^a ; Joseph F. Standing^c
• 关键词：F ; Bioavailability ; fa ; fraction absorbed ; fg ; fraction passing the gut wall ; fh ; fraction escaping hepatic metabolism ; GI ; gastrointestinal ; NLME ; nonlinear mixed effect modelling ; IR ; immediate release ; PR ; prolonged release ; ICH ; international conference on harmonisation ; GCP ; good clinical practice ; CLR ; renal clearance ; CLH ; hepatic clearance ; WT ; weight ; FQ ; liver blood flow ; BPR ; blood/plasma ratio ; CLi ; intrinsic clearance ; LV ; liver volume ; ER ; extraction ratio ; FOCE ; first order condit
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：30 June 2016
• 年：2016
• 卷：89
• 期：Complete
• 页码：50-60
• 全文大小：1320 K

文摘

Inter-subject variability in oral drug absorption is usually reported using bioavailability, which has the components: fraction absorbed (f_a), fraction passing the gut wall (f_g) and fraction escaping hepatic metabolism (f_h). In this study, we sought to separate the absorption (f_a ∗ f_g) and elimination (f_h) 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 f_a ∗ f_g 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 f_a ∗ f_g 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.