A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers

Clin Ther. 2003 Aug;25(8):2215-24. doi: 10.1016/s0149-2918(03)80214-x.

Abstract

Background: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been developed for the treatment of patients with dyslipidemia.

Objective: This study assessed the dose proportionality and pharmacokinetics of single oral doses of rosuvastatin in healthy volunteers.

Methods: This was a double-blind, randomized, incomplete crossover trial consisting of 3 trial days separated by >/=7-day washout periods. Healthy men were allocated to 1 of 2 treatment regimens: rosuvastatin 10, 20, and 80 mg, or rosuvastatin 10, 40, and 80 mg, administered as single doses on separate trial days in random order. Pharmacokinetic and tolerability assessments were made up to 96 hours after administration. Dose proportionality was tested using the power-law approach.

Results: Eighteen healthy white men participated in the trial (mean age, 41.2 years; mean height, 178.4 cm; mean body weight, 81.6 kg). Geometric mean rosuvastatin maximum plasma concentration (C(max)) values of 3.75, 6.79, 10.3, and 30.1 ng/mL were achieved at a median time to C(max) of 5.0 hours after doses of 10, 20, 40, and 80 mg, respectively. The corresponding geometric mean values for rosuvastatin area under the plasma concentration-time curve from time 0 to time of the last measurable concentration (AUC(0-t)) were 31.6, 56.8, 98.2, and 268 ng.h/mL. C(max) and AUC(0-t) were both linearly related to dose. The estimates of the proportionality coefficient (90% CI) for CmaX and AUC(o-t) were 0.999 (0.898-1.099) and 1.024 (0.941-1.107), respectively; all values fell within the prespecified range of 0.847 to 1.153. Rosuvastatin was well tolerated in this group of healthy men when administered orally at doses of 10 to 80 mg.

Conclusion: Rosuvastatin systemic exposure was dose proportional over the dose range of 10 to 80 mg.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Area Under Curve
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Fluorobenzenes / administration & dosage*
  • Fluorobenzenes / blood
  • Fluorobenzenes / pharmacokinetics
  • Half-Life
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics
  • Male
  • Middle Aged
  • Pyrimidines / administration & dosage*
  • Pyrimidines / blood
  • Pyrimidines / pharmacokinetics
  • Rosuvastatin Calcium
  • Sulfonamides / administration & dosage*
  • Sulfonamides / blood
  • Sulfonamides / pharmacokinetics
  • Time Factors

Substances

  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • Rosuvastatin Calcium