Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications

• DOI: 10.5588/ijtld.17.0697
• Publication Date: 2018-04-17T09:10:28Z
• Authors: R. Court; M. T. Chirehwa; L. Wiesner; B. Wright; W. Smythe; N. Kramer; H. McIlleron
• Keywords: Adult; Male; 0301 basic medicine; Cross-Over Studies; Dose-Response Relationship, Drug; Antitubercular Agents; Biological Availability; Original Articles; Healthy Volunteers; 3. Good health; Drug Combinations; South Africa; Young Adult; 03 medical and health sciences; Therapeutic Equivalency; Humans; Tuberculosis; Female; Rifampin; Tablets

Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure.We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0-12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings.Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0-12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69-89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97-111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients.Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.