Impact of Obesity and MASH on Zonal Hepatocellular Statin Exposure: Pharmacodynamic Insights From a Permeability‐Limited Multicompartment Liver Model

Statins are frequently prescribed for hyperlipidemia, a common comorbidity in patients with obesity and/or metabolic dysfunction‐associated steatohepatitis (MASH). However, limited knowledge exists on how MASH may alter statin disposition within hepatocytes where the statin target, 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase, is located. This study used a physiologically based pharmacokinetic (PBPK)/permeability‐limited multicompartment liver (PerMCL) framework, incorporating zonal transporter and drug‐metabolizing enzyme data. Systemic and hepatocellular concentrations of pravastatin, rosuvastatin, and atorvastatin were simulated in Healthy Volunteers (HV), Obese, Morbidly Obese, and MASH virtual populations with the Simcyp Simulator. A pharmacodynamic model in Simcyp Designer was then used to simulate alterations in rosuvastatin cholesterol‐lowering efficacy between these populations. Hepatic transport and metabolism pathways were verified against clinical data. Organic anion transporting polypeptide (OATP)1B model uptake pathways were verified using genotype and drug–drug interaction data. Atorvastatin metabolism pathways were verified using metabolite data. Steady‐state plasma and zonal hepatocellular concentration–time profiles for each statin were simulated across virtual populations of 100 individuals aged 40–65 years. Simulations predicted > 70% increases in maximal total plasma concentrations and area under the curve for pravastatin and rosuvastatin in MASH compared to HV, with changes in these parameters for atorvastatin simulated to increase > 250%. In MASH, unbound hepatocellular exposure increased by up to 127% in the periportal region for atorvastatin and decreased by up to 55% in the pericentral region for rosuvastatin. The pharmacodynamic model simulated decreased rosuvastatin cholesterol‐lowering efficacy in MASH compared with Obese, which could be compensated for with a 50% increase in dose according to exploratory simulations.