Pharmacokinetic comparison of controlled-release and immediate-release oral formulations of simvastatin in healthy Korean subjects: A randomized, open-label, parallel-group, single- and multiple-dose study

Abstract Background : A controlled-release (CR) formulation of simvastatin was recently developed in Korea. The formulation is expected to yield a lower Cmax and similar AUC values compared with the immediate-release (IR) formulation. Objective : The goal of this study was to compare the pharmacokinetics of the new CR formulation and an IR formulation of simvastatin after single- and multiple-dose administration in healthy Korean subjects. This study was developed as part of a product development project at the request of the Korean regulatory agency. Methods : This was a randomized, open-label, parallelgroup, 2-part study. Eligible subjects were healthy male or female volunteers between the ages of 19 and 55 years and within 20% of their ideal weight. In part I, each subject received a single dose of the CR or IR formulation of simvastatin 40 mg orally (20 mg × 2 tablets) after fasting. In part II, each subject received the same dose of the CR or IR formulation for 8 consecutive days. Blood samples were obtained for 48 hours after the dose in part I and after the first and the last dose in part II. Pharmacokinetic parameters were determined for both simvastatin (the inactive prodrug) and simvastatin acid (the active moiety). An adverse event (AE) was defined as any unfavorable sign (including an abnormal laboratory finding) or symptom, regardless of whether it had a causal relationship with the study medication. Serious AEs were defined as any events that are considered life threatening, require hospitalization or prolongation of existing hospitalization, cause persistent or significant disability or incapacity, or result in congenital abnormality, birth defect, or death. AEs were determined based on patient interviews and physical examinations. Results : Twenty-four healthy subjects (17 men, 7 women; mean [SD] age, 29 [7] years; age range, 22–50 years) were enrolled in part I, and 29 subjects (17 men, 12 women; mean age, 33 [9] years; age range, 19–55 years) were enrolled in part II. For simvastatin acid, Cmax was significantly smaller (1.68 vs 3.62 ng/mL; P < 0.013) and Tmax and apparent t½ significantly longer (10.33 vs 4.04 hours [ P < 0.001] and 11.41 vs 4.16 hours [ P < 0.011]) for the CR formulation compared with the IR formulation, respectively, after the single-dose administration. After the multiple-dose administration, for simvastatin acid, the Cmax for the CR formulation was significantly smaller (3.40 vs 5.16 ng/mL; P < 0.037), while the valu