Physiologically based pharmacokinetic modeling of caffeine in patients with liver cirrhosis: Implications for exposure-guided dose adjustment.

Caffeine exposure may increase substantially in patients with liver cirrhosis due to impaired hepatic metabolism, but quantitative approaches for predicting exposure changes and guiding dose adjustment remain poorly defined. A physiologically-based-pharmacokinetic (PBPK) model of caffeine was developed using literature-derived clinical PK data from healthy adults and subsequently extrapolated to Child-Pugh A (CP-A) and Child-Pugh B (CP-B) cirrhotic populations by incorporating disease-specific physiological and biochemical changes. Most predicted PK parameters satisfied predefined two-fold error criterion. Repeated-dose simulations demonstrated progressive increases in systemic caffeine exposure with worsening hepatic impairment. Exposure-based simulations predicted that approximately 51% and 18% of healthy-subject dose would achieve comparable systemic exposure in CP-A and CP-B patients, respectively. Sensitivity analysis identified CYP1A2-related parameters, liver volume, plasma protein scale factor, and fraction unbound as major determinants of caffeine exposure. The developed PBPK model successfully characterized caffeine PKs and supports a simulation-based framework for predicting caffeine exposure under hepatic impairment.