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Kim, Jimyon,Ahn, Byung‐,Jin,Chae, Hong‐,Seok,Han, Seunghoon,Doh, Kichan,Choi, Jeongeun,Jun, Yong K.,Lee, Yong W.,Yim, Dong‐,Seok Blackwell Publishing Ltd 2011 Basic & Clinical Pharmacology & Toxicology Vol.109 No.3
<P><B>Abstract: </B> 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.</P>