Fixed-dose combination (FDC) formulations for the treatment of tuberculosis are now being recommended by the World Health Organization and used worldwide for reducing the risk of emerging drug resistance. China also plans that the FDC coverage will be achieved 100% in 2015 in every county in the country. However, the quality of FDCs with respect to variable bioavailability is a major issue.
This study was conducted in healthy Chinese subjects to compare the bioavailability of rifampicin, isoniazid, ethambutol, and pyrazinamide from a 4-drug FDC formulation versus that of the separate formulations.
The study was designed as randomized, single-dose, 2-treatment, 2-period crossover trial with a washout period of 1 week. Blood samples were collected at 0 (baseline), 10, 20, and 40 minutes and at 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose. Plasma concentrations of the 4 drugs were measured by using a rapid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated by using noncompartmental methods. Bioequivalence was determined if the 90% CIs of the log-transformed test/reference ratios AUC(0-24), AUC(0-∞), and C(max) were within the predetermined range of 80% to 125%. Tolerability was assessed by using clinical parameters and subject reports.
A total of 18 male subjects (mean [SD] age, 36.4 [10.6] years) were enrolled and completed the study. In the case of rifampicin, the 90% CIs for the log-transformed ratios of C(max), AUC(0-24), and AUC(0-∞) were 81.8 to 100.9, 89.5 to 100.2, and 87.1 to 98.0, respectively. For ethambutol, these values were 84.7 to 105.7, 93.5 to 105.1, and 92.1 to 105.4. For pyrazinamide, these values were 83.3 to 93.9, 95.8 to 101.4, and 97.0 to 104.1. For isoniazid, the 90% CIs for the log-transformed ratios of AUC(0-24), and AUC(0∞) were 83.5 to 94.6 and 83.4 to 94.4. However, the point estimates for C(max) (62.2-86.7) were outside the limit for bioequivalence. No adverse events were observed during the study.
The findings from this single-dose study in healthy Chinese male volunteers suggest that the combined formulation was bioequivalent to separate formulations of rifampicin, ethambutol, and pyrazinamide at the same dose levels. However, isoniazid was not bioequivalent based on C(max) values. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451.