title: A population pharmacokinetic-pharmacodynamic model for simvastatin that predicts low-density lipoprotein-cholesterol reduction in patients with primary hyperlipidaemia.
abstract: Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and simvastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data.
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jimyon
authors.initials: J
authors.lastname: Kim
authors.forename: Byung-Jin
authors.initials: BJ
authors.lastname: Ahn
authors.forename: Hong-Seok
authors.initials: HS
authors.lastname: Chae
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
authors.forename: Kichan
authors.initials: K
authors.lastname: Doh
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Choi
authors.forename: Yong K
authors.initials: YK
authors.lastname: Jun
authors.forename: Yong W
authors.initials: YW
authors.lastname: Lee
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
mesh_terms: D000328:Adult; D001241:Aspirin / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D019821:Simvastatin / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D001241:Aspirin