Pharmacokinetic properties of rosuvastatin after single-dose, oral administration in Chinese volunteers: a randomized, open-label, three-way crossover study.

BACKGROUND: Rosuvastatin, a 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitor ("statin"), has been marketed for the treatment of patients with dyslipidemia.
OBJECTIVES: The objective of this study was to assess the dose proportionality and pharmacokinetic (PK) properties of rosuvastatin after single-dose administration in Chinese volunteers. The effects of food and sex on the PK properties of rosuvastatin in these volunteers were also assessed.
METHODS: This single-dose, randomized, open-label, 3-way crossover trial was conducted at West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China. Healthy, male and female, adult (aged 20-24 years), Han Chinese volunteers were enrolled. Volunteers were allocated to receive, in randomized order according to a computer-generated randomization schedule, single doses of rosuvastatin (5, 10, and 20 mg) administered in separate trial periods, with a 1-week washout between periods. PK properties (C(max), T(max), AUC(0-t), apparent elimination t(1/2)) and tolerability were assessed immediately before (0 hour) and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 15, 24, 36, 48, and 72 hours after study drug administration. The Student-Newman-Keuls test was used to test for linearity. The effects of food intake and sex on the PK properties of rosuvastatin were also investigated in subanalyses using standardized meals and the t test of logarithm-transformed (lg) values to detect differences in C(max) and AUC(0-t) between sexes and between the fed (test) and fasted (reference) states. All of the results were corrected for dose by weight (mg/kg).
RESULTS: The study enrolled 12 healthy Chinese volunteers (6 men: mean [SD] age, 22.3 [1.5] years; mean [SD] weight, 61.8 [2.4] kg [range, 59-64 kg]; 6 women: mean [SD] age, 21.6 [1.4] years; mean [SD] weight, 56.4 [6.4] kg [range, 50-64 kg]). Geometric mean (SD) C(max) values of 10.22 (8.05), 25.86 (18.77), and 44.99 (17.99) ng/mL were achieved at a median T(max) of 2.5 hours after administration of single doses of 5, 10, and 20 mg of rosuvastatin, respectively; the corresponding geometric mean (SD) values of AUC(0-t) were 73.67 (48.78), 210.21 (178.70), and 303.81 (193.29) ng/mL . h(-1), and the mean (SD) apparent elimination t(1/2) values were 13.01 (8.68), 13.33 (5.21), and 15.40 (5.43) hours after administration. The Student-Newman-Keuls test results found that C(max) and AUC(0-t) were both linearly related to dose. In men, the mean (SD) C(max) values were 7.57 (6.49), 20.43 (14.10), and 36.80 (15.64) ng/mL, and the mean (SD) AUC(0-t) values were 51.74 (33.92), 136.35 (97.18), and 232.25 (101.66) ng/mL x h(-1), with the 5-, 10-, and 20-mg doses of rosuvastatin, respectively. In women, the corresponding C(max) values were 13.40 (9.27), 32.44 (23.10), and 54.82 (16.78) ng/mL, and AUC(0-t) values were 99.99 (54.07), 298.85 (223.66), and 430.21 (194.61) ng/mL x h-1. Results of the t tests of (lg)C(max) and (lg)AUC(0-t) found no significant differences between the male and female groups. However, C(max) and AUC(0-t) values of 0.82 ng/mL and 6.87 ng/mL x h-1, respectively, after oral administration of 10 mg of rosuvastatin in the fed state were significantly different from the corresponding values under fasting conditions (both, P < 0.05). Two adverse events (pharyngitis and nausea) were reported in 3 subjects (2 women, 1 man) at the 20-mg fasting state. Two cases of elevated laboratory values (bilirubin, from 16.1 micromol/L at baseline to 31.4 micromol/L; phosphocreatine, from 141 U/L at baseline to 307 U/L) were found at the poststudy follow-up immediately after study completion in 2 volunteers (1 man, 1 woman) at the 10-mg fed state; both values had returned to normal 5 days later.
CONCLUSIONS: The PK properties of rosuvastatin are based on first-order kinetics in the dose range tested. In this small, selected group of healthy Chinese volunteers, no clinically significant differences in PK properties between doses or sexes were found. The absorption of rosuvastatin was significantly decreased in the fed state compared with the fasting state, which suggests that rosuvastatin should be administered on an empty stomach. All rosuvastatin doses tested were well tolerated.

RCT Entities:   Population Interventions Outcomes