{"doi":"10.1002/psp4.70138","title":"Impact of Obesity and <scp>MASH</scp> on Zonal Hepatocellular Statin Exposure: Pharmacodynamic Insights From a Permeability‐Limited Multicompartment Liver Model","abstract":"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.","journal":"CPT Pharmacometrics & Systems Pharmacology","year":2025,"id":554491,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":510039,"name":"Noora Sjöstedt","orcid":"0000-0001-6960-7757","position":1,"is_corresponding":false},{"id":1451807,"name":"Maïlys De Sousa Mendes","orcid":"0000-0001-5460-4350","position":2,"is_corresponding":false},{"id":1451808,"name":"Mattie Hartauer","orcid":"0000-0002-5082-0168","position":3,"is_corresponding":false},{"id":407251,"name":"Kim L. R. Brouwer","orcid":"0000-0003-1945-4929","position":4,"is_corresponding":false},{"id":416398,"name":"Sibylle Neuhoff","orcid":"0000-0001-8809-1960","position":5,"is_corresponding":false},{"id":798143,"name":"William A. Murphy","orcid":"0000-0002-7476-9248","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:54:50.112989Z","pmid":"41230730","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}