Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers

Authors


  • Rosuvastatin is licensed from Shionogi and Co. Ltd, Osaka, Japan.

  • Trials 4522IL/0048, 0012 and 0053, 0057, and 0058.

Dennis W. Schneck, AstraZeneca R & D Wilmington, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Fairfax OW3, PO Box 15437, Wilmington, DE 19850–5437, USA. Tel.: + 1 302 886 5904; Fax: + 1 302 886 1099; E-mail: dennis.schneck@astrazeneca.com

Abstract

Aims  To compare the lipid-regulating effects and steady-state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low-density lipoprotein cholesterol (LDL-C) concentrations < 4.14 mmol l−1.

Methods  In this open-label two-way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food.

Results  Reductions from baseline in serum concentrations of LDL-C (−41.3%[morning]vs−44.2%[evening]), total cholesterol (−30.9%vs−31.8%), triglycerides (−17.1%vs−22.7%), and apolipoprotein B (−32.4%vs−35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG-CoA reductase activity, decreased by −29.9% (morning) vs−32.6% (evening). Urinary excretion of MVA declined by −33.6% (morning) vs−29.2% (evening). The steady-state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml−1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml−1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration.

Conclusions  The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL-C.

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