Pharmacokinetic/pharmacodynamic characteristics of simvastatin and its associated factors in healthy Koreans
건강한 한국인에 있어서 심바스타틴의 약동력학적 특성과 그에 영향을 미치는 인자
Dept. of Medical Science/박사
Simvastatin is a widely used 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and has beneficial effects on coronary diseases and on decreasing mortality rates in patients with hypercholesterolemia. Large inter-individual variability in the concentrations and pharmacokinetic parameters of simvastatin makes it difficult to achieve effective treatment and to avoid toxicity. This suggests that therapeutic drug monitoring of simvastatin is required, and individual optimal dosage regimen should be proposed and initiated as early as possible.This study was aimed to develop the population pharmacokinetic and pharmacodynamic models of simvastatin, as well as to assess the effect of demographic and clinical covariates which might influence on the pharmacokinetics and the pharmacodynamics of simvastatin in Korean population.This study was composed of four parts. Part I was a 40 mg single-dose study in twelve healthy subjects, and Part II and III were a 40 mg multiple-dose studies during 8 and 9 days in fourteen and forty one healthy subjects, respectively. These three Parts were performed to determine the pharmacokinetics of simvastatin. Blood samples were obtained before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 13, 17, 24, 36, and 48 hours after the dose in Part I, or after the first (day 1) and the last dose (day 8) in Part II, or after the last dose (day 9) in Part III to determine the simvastatin and the simvastatin acid concentrations. The compartment model for simvastatin and simvastatin acid was used to describe their pharmacokinetics. Part IV was a 20(n=9), 40(n=9) or 60(n=7) mg multiple-dose study during 28 days in twenty five healthy subjects. In Part IV, blood samples of 8 mL each were prepared in heparinized tubes before and at 1, 3, 6, 10, 14, 21, 28 days after the first dosing to determine the LDL level and to describe the pharmacodynamic of simvastatin.Simvastatin pharmacokinetics was best described by two-compartment model with first-order absorption, and simvastatin acid pharmacokinetics was linked directly to the central compartment of simvastatin using the metabolic rate constant, k24. In the final model, the estimate of Ka was 3.15 1/h in Part III, and 0.60 1/h in Part I and II. The estimate of V2 was 1660 L in Part III, and 2760 L in Part I and II. The estimate of K24 was 0.29 1/h in Part III, and 0.46 1/h in Part I and II. Other parameter did not differ much between Parts. Intra-individual variabilities were 44% and 39% for simvastatin and simvastatin acid, respectively. None of the covariates tested (age, weight, sex, smoke, alcohol, and C1236T, C3456T, G2677T/A genotypes of MDR1) was found significant in the pharmacokinetics of simvastatin and simvastatin acid.Simvastatin pharmacodynamics was described by the inhibitory kin type of indirect response model. In the final model, the estimates of R0 for 20 mg, 40 mg and 60 mg groups were 78.2, 111 and 132 mg/dL, respectively. The percent change of predicted LDL did not differ significantly among the three dose group at 28 days (p=0.1695). No covariate was found significant for any pharmacodynamic parameter.These preliminary results show that simvastatin pharmacokinetics in Korean adults might be described without considering covariate influences and its steady-state pharmacodynamics can be predicted similarly for a range of therapeutic doses. Further studies will be needed to validate the proposed results.