Drug interaction of rifampicin on fluconazole in AIDS patients : pharmacokinetics and clinical observations

Abstract

Rifampicin and fluconazole may be co-administered in a number of clinical situations of opportunistic infection treatment in AIDS patients and the magnitude of the interaction between these two drugs may have a significant impact on the therapeutic outcome of patients. The purposes of this study were to study the effect of rifampicin on the pharmacokinetics of fluconazole along with some of its clinical outcome by compared the pharmacokinetic parameters between a group of patients who received only fluconazole and a group of patients who co-administered fluconazole with rifampicin. The effects of interaction on clinical outcome were studied by observations on the difference in time to negative culture for Cryptococcus neoformans in CSF between two groups. The study was carried in forty cryptococcal meningitis patients with AIDS, at Bamrajnaradura Hospital, divided in equal number of twenty in each groups. Most of the patients were male (70%) ranging in aged from 21-48 years. For the first 2 weeks, all of patients were received amphotericin B (0.7 mg/kg/day), then fluconazole 400 mg/day were given to all patients. Blood sample from the first twelve patients enrolled in each group were collected in 3 periods (period I: on the day 8 of fluconazole 400 mg/day, period II on the day 15, period II on the day 8 of fluconazole 200 mg/day). Pharmacokinetic parameters were generated from fluconazole concentrations RSTRIP program. This study found that concomitant administration of rifampicin with fluconazole resulted in significantly changed in the pharmacokinetic parameters of fluconazole. These changes included 39.08% increase in Ke, 28.19% decrease in half-life, 22.48% decrease in AUC (0-24), 17.41% decrease the maximum concentration (Cmax) and 29.99 increase in clearance (P<0.05). The mean Ke derived from concentrations obtained in period I, II and III were not significantly different (P>0.05 by repeated-measures analysis of variance) indicated that the extent of interaction was complete and stable, did not change with time and doses of fluconazole. There were no significant differences in CSF components between the two groups. The abnormal mean protein and mean glucose changed to normal range within week 3 of the therapy. CSF white blood cell count and OP slowly decrease to normal ranges in both groups. CSF culture of all patients became negative within 6 weeks. There were no significant differences in the conversion rates of CSF culture between the two groups (P=0.792). Comparison of fluconazole pharmacokinetic parameters between groups of patients who had different conversion rates (3 weeks, 4 weeks and 6 weeks) showed no significant differences. Since amphotericin B had been given during the first 2 weeks as an initial therapy for cryptococcal meningits and fluconazole concentrations in the dosage of 400 mg/day were high above in MIC range, the clinical outcome turn out to be the same even though the concentrations and pharmacokinetic parameters of fluconazole changed significantly when co-administered with rifampicin. The mean serum concentrations of fluconazole in patients who received rifampicin concomitantly with fluconazole were lower than MIC, long term monitoring for recurrent rates of cryptococcal meningitis before any conclusion could be made on whether the 30% decrease in clearance of fluconazole from rifampicin will cause any significant effects on clinical outcome of fluconazole.