Insights into Drug Absorption Impairment Mechanisms in Hepatic Impairment using Physiologically-based Pharmacokinetic Modelling: A Case Study with Nilotinib.

Abstract

Nilotinib is reported to have a reduced maximal drug concentration (C_max) in patients with hepatic impairment (HI). Given this compound is poorly soluble, highly lipophilic and has a positive food effect, reduced absorption in HI may be due to impaired micelle-mediated solubility resulting from reduced intestinal bile salts. PBPK modelling can be used to test this hypothesis as well as being a diagnostic tool to elucidate other potential mechanisms not captured by the base model. In this study, a mechanistic PBPK model for nilotinib was developed and its performance was evaluated in HI patients. A 'learn-and-confirm' approach was taken, using clinical food effect data to validate the model's mechanistic sensitivity to bile salt-mediated solubility. The final model recovered clinical studies well, with area-under-the-curve (AUC) and C_max being within 0.8 - 1.25-fold for fasted studies and 1.5-fold for fed/fasted ratios. AUC and C_max were well recovered in mild HI (within 0.8 - 1.25-fold) and reasonably well recovered in moderate HI (within twofold) but significantly overpredicted in severe HI (> twofold). Bile salt concentrations were reduced across gastrointestinal segments for moderate and severe HI in line with in vitro data. Following twofold and 2.5-fold reductions in bile salts in moderate and severe HI, respectively, sensitivity was minor. Given uncertainty around the fu_gut, this was reduced to better recover the C_max (within two-fold). PBPK modelling can be used as a diagnostic tool to evaluate impaired mechanisms in HI.