Results of a single-center, single-dose, randomized-sequence, open-label, two-way crossover bioequivalence study of two formulations of valsartan 160-mg tablets in healthy volunteers under fasting conditions.

摘要

BACKGROUND: Valsartan is a nonpeptide, orally active angiotensin II type 1 receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents. OBJECTIVE: The aim of this study was to compare the relative bioavailability of a new valsartan 160-mg formulation (ie, test drug) and that of a reference formulation so that bioequivalence could be assessed, as required by European regulatory authorities for the marketing of a generic product. METHODS: This was a single-center, single-dose, randomized-sequence, open-label, 2-way crossover study with a minimum washout period of 7 days; drug was administered to healthy volunteers under fasting conditions. Blood samples were collected up to 36 hours postadministration, and valsartan levels were gauged from plasma by reverse liquid chromatography and tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated from valsartan concentration data using noncompartmental analysis. AUC(last), AUC(infinity), and C(max) were analyzed. The 90% CIs of the ratios of the test-versus-reference pharmacokinetic parameters (AUC(last), AUC(infinity), and C(max)) were obtained by ANOVA on ln-transformed data. The 90% CIs were required to be within 80.00% to 125.00% of the 90% CI to meet the criteria for bioequivalence. Tolerability was monitored using physical examination (including vital-sign measurements) and ECG performed at screening, as well as laboratory analysis, including biochemistry tests, hematology tests, and urinalysis, which were performed at screening and during the study period. RESULTS: Thirty-eight white (90.5%), 2 black (4.8%), and 2 Hispanic subjects (4.8%) enrolled in the study; the sample included a total of 27 men and 15 women. The mean (SD) age was 37 (11) years and mean weight was 65.4 (7.6) kg. The 90% CI values for pharmacokinetic measurements were as follows: AUC(last), 94.45% to 118.59%; AUC(infinity), 93.58% to 116.51%; and C(max), 93.61% to 122.02%. Thus, they were all within the predefined 80.00% to 125.00% range. Thirty-six postadministration adverse events were reported; the most common was blood pressure decrease. A decrease of blood pressure was experienced by 6 subjects (14.6%) after the administration of the test formulation, and by 5 subjects (12.5%) after the administration of the reference formulation. Thirty-three of these adverse events were graded as mild and 3 as moderate; 11 were judged as probably related, 12 as possibly related, 3 as remotely related, and 10 as unrelated to the study medication. CONCLUSIONS: In this open-label study of healthy volunteers, the test and reference formulations of valsartan 160 mg met the European regulatory definition of bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated.