Physiologically based pharmacokinetic modeling for optimal dosage prediction of statins and warfarin in patients with liver cirrhosis.

purposeLiver cirrhosis is a chronic disease that can change the pharmacokinetics of many drugs. Physiologically-based pharmacokinetic (PBPK) modeling and simulation can help in predicting the disposition of many drugs in special populations, including cirrhosis. Limited information is available on statins (simvastatin, rosuvastatin, and atorvastatin) and warfarin doses in cirrhosis. This study aims to use PBPK modeling to provide some guidance on the optimal doses of these medications in cirrhotic patients.

methodsInitially, the developed PBPK models were evaluated against available clinical pharmacokinetic data from healthy subjects and patients with cirrhosis. Subsequently, simulations were extrapolated to predict drug exposures in various untested cirrhosis populations, stratified by Child–Pugh classes A, B, and C. Dose adjustments for cirrhotic patients were evaluated to achieve unbound drug exposures equivalent to those observed in healthy volunteers.

resultsThe models effectively captured the pharmacokinetics of the studied drugs in healthy populations within an acceptable 2-fold range. The models indicated gradual increases in unbound drug exposure with disease progression. The simulation results suggested decreasing doses of simvastatin, rosuvastatin, and atorvastatin by approximately 61%, 65%, and 70% in CP-A, 85.5%, 76%, and 84% in CP-B, as well as 93.5%, 85%, and 92% in CP-C to match healthy exposure levels. Additionally, warfarin doses can be reduced by 33.3% and 66.6% of the healthy dose in CP-B and CP-C, respectively.

conclusionPBPK models can help in predicting statins and warfarin disposition in patients with cirrhosis, aiding in clinical study design and expanding therapeutic options for those patients.