THE AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE FOR ORAL MIDAZOLAMIS 400-FOLD LARGER DURING TREATMENT WITH ITRACONAZOLE THAN WITH RIFAMPICIN

Objective: To determine the effects of treat ment with itraconazole an d rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics o f oral midazolam during and 4 days after the end of the treatment. Met hods: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In a ddition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disp osition of midazolam and its alpha-hydroxy metabolite was determined a nd its pharmacodynamic effects were measured.Results: During itraconaz ole treatment, or 4 days after, alpha-hydroxymetabolite the dose-corre cted area under the plasma midazolam concentration-time curve (AUC(0-i nfinity)) was 8- or 2.6-fold larger than that before itraconazole (i.e . 1707 or 695 versus 277 ng.h.ml(-1)), respectively. One day after rif ampicin treatment, the AUC(0-infinity) of midazolam was 2.3% (i.e. 4.4 ng.h.ml(-1)) of the before-treatment value and only 0.26% of its valu e during itraconazole treatment; il days after rifampicin, the AUC(0-i nfinity) was still only 13% (i.e. 27.1 ng.h.ml(-1)) of the before-trea tment value. The peak concentration and elimination half-life of midaz olam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma alpha-hydroxymidazolam to midazolam was greatly de creased by itraconazole and increased by rifampicin. In addition, the effects of midazolam mere greater during itraconazole and smaller 1 da y after rifampicin than without treatment. Conclusion: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During ora l administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatmen t. After cessation of treatment with itraconazole or rifampicin, the r isk of significant interaction continues up to at least 4 days, probab ly even longer.