Impact of Obesity and MASH on Zonal Hepatocellular Statin Exposure: Pharmacodynamic Insights From a...

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.