LACK OF EFFECT OF CONCOMITANT ZIDOVUDINE ON RIFABUTIN KINETICS IN PATIENTS WITH AIDS-RELATED COMPLEX

The effect of concomitant dosing with the antiretroviral agent zidovud ine (ZDV) on the pharmacokinetics of rifabutin (RBT) was investigated under steady-state conditions, Sixteen human immunodeficiency virus-po sitive patients with AIDS-related complex who had been maintained on s table ZDV therapy for greater than or equal to 6 weeks were administer ed RBT concomitantly for 12 days, Eight patients received daily doses of 300 or 450 mg of RBT, Administration of ZDV was discontinued on day 13, and RBT was given alone for 3 additional days. Four patients rece iving 450 mg of RBT discontinued treatment, Under steady-state ZDV and RBT dosing, safety and kinetics assessments were performed on day 13 (ZDV plus RBT) and day 16 (RBT alone). Kinetics on days 13 and 16 demo nstrated that RBT (300 or 450 mg) was readily absorbed, with the time at which the plasma concentration was maximal (T-max) ranging between 2.6 and 2.9 h. At these two doses, the mean steady-state maximal plasm a concentrations (C-max) were 250 and 430 ng/ml on day 13 and 245 and 458 ng/ml on day 16, respectively. RBT kinetics at the two doses were proportional and similar on the basis of estimates of the ratios of th e areas under the concentration-time curves over the dosing interval f rom 0 to 24 h (AUC(0-24)) (450 mg/300 mg), which were 1.5 and 1.4 for days 13 and 16, respectively, No significant differences were apparent in the mean oral clearance (CL(S)/F) estimates (range, 1.60 to 1.77 l iters/h/kg), which were dose independent and similar for the 2 assessm ent days, as was the urinary recovery of RBT and its 25-deacetyl metab olite, Low urinary recovery of 25-deacetyl RBT and an AUC metabolite/p arent ratio of 0.1 suggest that there is minimal metabolism of RBT via the deacetylation pathway, For RBT, pooled mean (95% confidence inter val) ratio (day 13/day 16) estimates for C-max, T-max, AUC(0-24), and CL(S)/F were 1.07 (range, 0.77 to 1.38), 1.08 (0.89 to 1.27), 0.97 (0. 82 to 1.13), and 1.09 (0.92 to 1.26), respectively. In addition, no si gnificant changes in any of the major safety parameters were detected throughout the study, Therefore, it is concluded that coadministration of ZDV and RBT does not affect the pharmacokinetics and/or safety of RBT in human immunodeficiency virus-positive patients.