Incorporation and performance verification of hepatic portal blood flow shunting in minimal and full PBPK models of liver cirrhosis.

Patho-physiological changes in liver cirrhosis create portacaval shunts that allow blood flow to bypass the hepatic portal vein into the systemic circulation affecting drug pharmacokinetics (PK). The objectives of this work were to implement a Physiologically Based Pharmacokinetic (PBPK) framework describing shunted blood flows in virtual patients with differing degrees of liver cirrhosis; and to assess the minimal and full PBPK models performance using drugs with intermediate to high hepatic extraction. Single dose concentration-time profiles and PK parameters for oral Ibrutinib, midazolam, propranolol and buspirone were simulated in Healthy-Volunteer (HV) and subjects with cirrhosis (Child-Pugh severity score A, B or C). Model performance was verified by comparing predicted to observed fold-changes in PK parameters between healthy volunteer and cirrhotic subjects. The verified model was used to simulate the PK changes for simvastatin in cirrhotic patients. The predicted AUC Cirr :AUC HV ratios for Ibrutinib were 3.38, 6.87 and 11.46 using the minimal PBPK model with shunt and 1.61, 2.58 and 4.33 without the shunt, these compared to observed values of 4.33, 8.14 and 9.04, respectively. For ibrutinib, propranolol and buspirone including a shunt in the PBPK model improved the prediction of the AUC Cirr :AUC HV and Cmax Cirr :Cmax HV ratios. For midazolam, an intermediate extraction drug, the differences were less clear. Simulated simvastatin dose adjustments in cirrhosis suggested that 20mg in CP-A and 10mg in CP-B could be used clinically. A mechanistic model-informed understanding of the anatomical and patho-physiology of cirrhosis will facilitate improved dose prediction and adjustment in this vulnerable population.