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

S E T T I N G: 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. O B J E C T I V E S A N D D E S I G N: 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 (AUC 0-12 ) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings. R E S U L T S: Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m 2 ) completed the study. The AUC 0-12 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. C O N C L U S I O N: Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.