Study of the interaction between rifapentine and isoniazid under acid conditions

Update in Tuberculosis 2006

“…Prasad and coworkers (43) studied the interaction between rifapentine and isoniazid under acid conditions; their findings suggest that coadministration of rifapentine and isoniazid should be avoided under such situations. The findings by Blake and coworkers (44) of lower rifapentine exposure estimates in children, given a comparable weight-normalized dose as for adults, would suggest the need for a larger milligram/kilogram dose of rifapentine in pediatric patients.…”

Formulation and Statistical Optimization of a Novel Crosslinked Polymeric Anti‐Tuberculosis Drug Delivery System

“…RIF is known to undergo hydrolysis in acidic medium to the insoluble 3‐formyl rifamycin SV (3‐FRSV). INH accelerates degradation of RIF into this poorly absorbed derivative (3‐FRSV) in the acidic environment of the stomach via reversible formation of the isonicotinyl hydrazone of 3‐FRSV with INH 9–16. The hydrazone, due to its instability in acidic conditions, regenerates INH and 3‐formylrifamycin by a pseudo first‐order reaction.…”

“…In comparison to pure drugs and their mixtures, wide variations in the decomposition of RIF (7.5–33.3%) and INH (1.4–5.3%) were seen in the marketed FDC products evaluated, indicative of the contributory effect of critical formulatory factors in FDC development 13. Prasad et al16 recently undertook and reported on pH‐decomposition studies for the combination of rifamycins (RIF and rifapentine) and INH. Both the drugs showed bell‐shaped pH‐dependent decomposition, with maximum degradation occurring at pH 2, the loss of rifamycins and INH being ≈30–33% and ≈9–10%, respectively after 50 min.…”

“…There is undoubtedly an in vitro drug interaction between RIF and INH under acidic conditions 10–12, 16, 17. Whether this interaction is clinically significant in vivo still remains to be indisputably proven.…”

“…Despite literary contradictions as to its overall importance in vivo , the stated interaction is, nonetheless, responsible, at least in part, for the fall in bioavailability of RIF from FDC products containing RIF or its derivatives (e.g., rifapentine) and INH, and the decomposition of RIF in the stomach prior to absorption is a strong contributory factor to treatment failure and emergence of resistance 16, 17. The reported levels of RIF decomposition following administration in the fasting state culminate in a reduction in the dose from ≈10 to 12 mg/kg (600 mg for patients above 60 kg and 450 mg for patients below 50 kg of body weight) to as low as 5–6 mg/kg of body weight 13.…”