Pharmacokinetics and bioequivalence evaluation of two losartan potassium 50-mg tablets: A single-dose, randomized-sequence, open-label, two-way crossover study in healthy Chinese male volunteers

Background: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population.

Objective: To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers.

Methods: A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including C(max), AUC(0-36), and AUC(0-infinity), were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of C(max) was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China.

Results: Twenty-seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20-29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m(2) [range, 20.0-25.0 kg/m(2)]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of C(max), AUC(0-36), and AUCAUC(0-infinity) were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of C(max), AUC(0-36), and AUCAUC(0-infinity) were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both C(max) and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174.

Conclusions: In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated.