Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers

• Published in: Clinical therapeutics 2003-10, Vol.25 (10), p.2553-2563
• Main Authors: Martin, Paul D., Warwick, Mike J., Dane, Aaron L., Brindley, Charlie, Short, Tracy
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Area Under Curve; Bioavailability; Biological and medical sciences; Biological Availability; Cholesterol; Cross-Over Studies; Fluorobenzenes - adverse effects; Fluorobenzenes - blood; Fluorobenzenes - pharmacokinetics; General and cellular metabolism. Vitamins; Half-Life; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - blood; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Infusions, Intravenous; Lipoproteins; Male; Medical sciences; Middle Aged; Pharmacokinetics; Pharmacology. Drug treatments; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Rosuvastatin Calcium; Statins; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Time Factors
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/S0149-2918(03)80316-8

Background: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated. Objectives: The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. Methods: This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a ≥7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastain 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing. Results: Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21–51 years), their mean height was 177 cm (range, 169–182 cm), and their mean body weight was 77.6 kg (range 68–85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%, and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for ≈28% of total plasma clearance (48.9 L/H). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers. CL p of rosuvastatin (48.9 L/h), pravastatin (∼60 L/h 20), fluvastatin (∼70 L/h 21), atorvastatin (37.5 L/h 22), and simvastatin (31.8 L/h 24) is higher than that of cerivastatin (12.9 L/h 23). To our knowledge, CL r data have been published only for pravastatin (>400 mL/min) which, like resuvastatin, is actively secreted by the kidney. 20 The pharmacokinetics of rosuvastatin observed in this trial are consistent with those reported elsewhere. 11–16 It should be noted that this trial was performed in healthy volunteers under carefully controlled conditions. The inclusion/exclusion criteria and dietary/lifestyle restrictions employed affect the ability to extrapolate the results to the general population.