EFFECT OF ITRACONAZOLE AND TERBINAFINE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF MIDAZOLAM IN HEALTHY-VOLUNTEERS

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomo tor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration-time curve six-fold (P < 0.001 ), the peak concentration 2.5-fold (P < 0.001) and the elimination hal f-life two-fold (P < 0.001) compared with placebo and terbinafine pret reatments. The pharmacokinetic parameters did not differ between place bo and terbinafine phases. The higher concentrations of midazolam duri ng the itraconazole phase were associated with increased effects. In c ontrast to itraconazole, terbinafine had no effect on midazolam pharma cokinetics and psychomotor performance tests were unchanged from place bo.