Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences

Background Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles. Methods In a double‐blind, 5‐way crossover study, healthy volunteers received (A) ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg ketoconazole twice a day plus 1.0 mg alprazolam, (C)ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. Results For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half‐life (t½ prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8‐hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit‐symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t½ was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8‐hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of ketoconazole. Conclusion For triazolam, an intermediate‐extraction compound, impaired clearance by ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound. Clinical Pharmacology & Therapeutics (1998) 64, 237–247; doi: