The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study

• Published in: Clinical therapeutics 2010-08, Vol.32 (9), p.1674-1680
• Main Authors: Li, Kun-Yan, PhD, Liang, Jian-Ping, BS, Hu, Bing-Qiang, PhD, Qiu, Yu, MS, Luo, Chen-Hui, MS, Jiang, Yun, BS, Lin, Xiao-Ping, BS, Yang, Nong, MS
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin II Type 1 Receptor Blockers - pharmacokinetics; Area Under Curve; Bioavailability; Bioequivalence; Biological and medical sciences; Biological Availability; Capsules; China; Chromatography; Cross-Over Studies; Drug dosages; Fasting; Humans; Hypertension; Imidazoles - administration & dosage; Imidazoles - adverse effects; Imidazoles - pharmacokinetics; Internal Medicine; Male; Mass spectrometry; Medical Education; Medical sciences; Metabolism; Olmesartan Medoxomil; Pharmacokinetics; Pharmacology. Drug treatments; Prodrugs; Scientific imaging; Tablets; Tetrazoles - administration & dosage; Tetrazoles - adverse effects; Tetrazoles - pharmacokinetics; Therapeutic Equivalency; UPLC-MS/MS; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2010.08.004

Abstract Background: Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. Objective: This study investigated the relative bioavail-ability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. Methods: This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of Cmax , AUC0–t , and AUC0–∞ were within the predetermined equivalence range (70%–143% for Cmax ; 80%–125% for AUC0–t and AUC0–∞ ), as established by the Chinese State Food and Drug Administration. Results: Twenty-one healthy male subjects (mean age, 21 years [range, 18–25 years]; weight, 62.1 kg [range, 54.0–80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC0–∞ values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for Cmax , AUC0–48 , and AUC0–∞ were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related advers