Lack of a pharmacologic interaction between rifabutin and methadone in HIV-infected former injecting drug users.

Rifampin, an agent known to decrease the half-life of methadone, and rifabutin are two rifamycins that are structurally similar and share mechanisms of action. Hence the possibility of a drug-drug interaction between rifabutin and methadone was evaluated in 24 methadone-maintained, former injecting drug users infected with the human immunodeficiency virus. The study was an open-label, drug-drug interaction and safety trial in which patients were followed for 15 days. Each patient received rifabutin 300 mg as a single dose concomitantly with their individualized methadone dosage. No significant differences in methadone peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, systemic clearance or renal clearance was observed in the presence of rifabutin. Seventy-five percent of the patients reported at least one symptom of narcotic withdrawal during the study, however, these symptoms were mild. A relationship between the development of narcotic withdrawal and methadone systemic exposure could not be established. Concurrent administration of rifabutin and methadone appeared to be safe in human immunodeficiency virus-infected injecting drug users maintained on stable doses of methadone and is not expected to produce any significant changes in the pharmacokinetics of methadone in these patients.

Lack of effect of concomitant zidovudine on rifabutin kinetics in patients with AIDS-related complex.

The effect of concomitant dosing with the antiretroviral agent zidovudine (ZDV) on the pharmacokinetics of rifabutin (RBT) was investigated under steady-state conditions. Sixteen human immunodeficiency virus-positive patients with AIDS-related complex who had been maintained on stable ZDV therapy for > or = 6 weeks were administered 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 receiving 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 demonstrated that RBT (300 or 450 mg) was readily absorbed, with the time at which the plasma concentration was maximal (Tmax) ranging between 2.6 and 2.9 h. At these two doses, the mean steady-state maximal plasma concentrations (Cmax) 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 the areas under the concentration-time curves over the dosing interval from 0 to 24 h (AUC0-24) (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 (CLs/F) estimates (range, 1.60 to 1.77 liters/h/kg), which were dose independent and similar for the 2 assessment days, as was the urinary recovery of RBT and its 25-deacetyl metabolite. Low urinary recovery of 25-deacetyl RBT and an AUC metabolite/parent ratio of 0.1 suggest that there is minimal metabolism of RBT via the deacetylation pathway. For RBT, pooled mean (95% confidence interval) ratio (day 13/day 16) estimates for Cmax, Tmax, AUC0-24, and CLs/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 significant 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.

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178.

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.