KETOCONAZOLE INHIBITION OF TRIAZOLAM AND ALPRAZOLAM CLEARANCE - DIFFERENTIAL KINETIC AND DYNAMIC CONSEQUENCES

Background: Kinetic and dynamic consequences of metabolic inhibition w ere 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 crossove r 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 concen trations 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 (t( 1/2)) prolonged (59 versus 15 hours; P <.03), whereas peak plasma conc entration (C-max) 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 cle arance was reduced (40 versus 444 dl/min; P <.002), t(1/2) was prolong ed (18.3 versus 3.0 hours; P <.01), and C,, 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. Ob served in vivo clearance decrements due to ketoconazole were consisten t with those anticipated on the basis of an in vitro model, together w ith in vivo plasma concentrations of ketoconazole. Conclusion: For tri azolam, an intermediate-extraction compound, impaired clearance by ket oconazole has more profound clinical consequences than those for alpra zolam, a low extraction compound.