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 (Cmax) 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 Cmax being within 0.8 – 1.25-fold for fasted studies and 1.5-fold for fed/fasted ratios. AUC and Cmax 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 fugut, this was reduced to better recover the Cmax (within two-fold). PBPK modelling can be used as a diagnostic tool to evaluate impaired mechanisms in HI. PBPK modelling of nilotinib in cirrhosis. A physiologically-based pharmacokinetic (PBPK) model for nilotinib with mechanistic absorption has been validated in healthy subjects using food effect studies. Model performance was then evaluated in hepatic impairment. Where mispredictions were observed, intestinal bile salts were reduced inline with physiological observations. Alternatively, increased gut binding was identified as a potential source for reduced absorption in these patients. PBPK modelling has been proposed as a diagnostic tool for understanding absorption impairment mechanisms in hepatic impairment. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0.