Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate

Abstract

Objective: To study the effect of rifampin (INN, rifampicin), a potent inducer of cytochrome P450, on the steady-state pharmacokinetics of delavirdine.

Methods: Twelve patients who were positive for human immunodeficiency virus, with CD4 counts ranging from 110 to 483/mm3, were randomized to two groups and studied in parallel. Both the control group (n = 5) and the rifampin group (n = 7) received 400 mg delavirdine mesylate every 8 hours for 30 days; subjects in the rifampin group took a 600 mg once-daily dose of rifampin on days 16 through 30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations with a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifampin by HPLC.

Results: Delavirdine mesylate alone and in combination with rifampin was well tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (p < 0.049). In the rifampin group, delavirdine oral clearance increased by about 27-fold (p = 0.022), resulting in virtually negligible (< 0.09 mumol/L) steady-state through drug concentrations in all patients after 2 weeks of concurrent dosing of delavirdine mesylate and rifampin. The ratio of metabolite formation to elimination clearance for desalkyldelavirdine was significantly higher (3.9 +/- 1.2 versus 0.23 +/- 0.10) and delavirdine elimination half-life was significantly shorter (1.7 +/- 1.4 versus 4.3 +/- 1.3 hours) when delavirdine mesylate was taken with rifampin. Rifampin pharmacokinetic parameters on days 16 and 30 were similar to those previously reported for normal volunteers.

Conclusions: The findings of this study indicate that rifampin induces the metabolism of delavirdine. Therefore therapy with rifampin is contraindicated in patients receiving delavirdine mesylate.