Pharmacokinetics and tolerability of multiple-dose rosuvastatin: An open-label, randomized-sequence, three-way crossover trial in healthy Chinese volunteers

Abstract

Background: Rosuvastatin has been reported to be beneficial in the treatment of dyslipidemia. The Cmax and AUC0-t of rosuvastatin were reported to be ~2 to 4 times higher in Chinese subjects compared with white subjects after administration of a single 1-mg/kg dose.

Objectives: The aims of this study were to assess the pharmacokinetics and tolerability of multiple doses of rosuvastatin in healthy Chinese volunteers.

Methods: This open-label, randomized-sequence, 3-way crossover trial consisted of three 7-day treatment periods and two 10-day washout periods. Healthy volunteers were randomly allocated to 1 of 3 daily treatment regimens: rosuvastatin 5, 10, or 20 mg. To assess the pharmacokinetics and tolerability of rosuvastatin, blood samples were drawn before dosing (hour 0) on days 5, 6, and 7 and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 15, 24, 36, 48, 72, and 96 hours after the final dose was administered on day 7. A validated HPLC-MS/MS method was used to determine rosuvastatin levels. A 2-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer. Adverse events (AEs) were monitored throughout the study via subject interview, vital signs, and blood sampling. Serious AEs were those requiring hospitalization, treatment discontinuation, or resulting in death.

Results: Twelve healthy Chinese volunteers (6 men: mean [SD] age, 21.8 [1.7] years; weight, 62.3 [5.8] kg; height, 174.3 [7.2] cm; 6 women: age, 20.8 [1.2] years; weight, 53.2 [4.7] kg; height, 161.3 [4.3] cm) participated in and completed the trial. The mean (SD) steady-state Cmax was significantly greater after ro-suvastatin administration in the 20-mg group compared with the 5-mg group (37.69 [29.83] vs 6.17 [6.03] ng/mL; P = 0.04). The t1/2 was significantly greater in the 20-mg group (15.51 [6.43] hours) compared with the 5-mg group (5.65 [5.08] hours; P = 0.001) and the 10-mg group (8.58 [5.17] hours; P = 0.002). The mean AUC0-t was significantly greater in the 20-mg group compared with the 5-mg group (349.16 [257.20] vs 40.63 [39.31] ng/mL/h; P = 0.02). All AEs were considered by the investigators to be mild in intensity, with the exception of 2 cases of abdominal discomfort (1 man and 1 woman, both in the 5-mg dose group). Two women in the 20-mg group experienced dizziness and cold sweats simultaneously. In the 10-mg group, 1 woman had abdominal discomfort and nausea and 1 woman had jaw pain. All reported AEs were considered possibly related to study drug administration.

Conclusions: In this small study in healthy Chinese volunteers, rosuvastatin systemic exposure appeared to be dose-proportional over the dosing range of 5 to 20 mg with multiple-dose administration. There was no accumulation of rosuvastatin in the body with the 5- and 10-mg doses. However, the results suggest that rosuva-statin might accumulate when the dose is increased to 20 mg. No serious AEs occurred in any of the 3 dosing groups.

Keywords: Chinese; multiple doses; pharmacokinetics; rosuvastatin; tolerability.