Dose dependent inhibition of midazolam elimination by ketoconazole: Effect of CYP3A5 genotype

Aims Ketoconazole (K), a potent inhibitor and substrate of CYP3A enzymes, is commonly used to determine the worst‐case drug interaction for CYP3A substrates. The effect of K dose and CYP3A5 genotype on in vivo CYP3A activity was assessed using the probe drug, midazolam (M). Methods 15 healthy volunteers (12 male), weighing (mean±SD) 76±12kg, completed a 3‐phase, randomized, crossover study. Intravenous (IV, 0.05mg/kg over 30 minutes) and oral (4mg) M were administered on separate days before and during 7 days of dosing with K 200 or 400mg (K 1hr prior to IV M on day 6 and oral M on day 7). Serum samples were assayed for M and K by HPLC‐MS. CYP3A5 genotype was obtained by allele‐specific real‐time PCR. Results The baseline AUCs after IV and oral M were 149±29 and 45±16μg×L/hr. The baseline oral bioavailability, systemic and oral clearance of M were 0.27±0.06, 26±6L/hr and 99±32L/hr, respectively. The average steady state concentration of K after 200mg and 400mg dosing was 1.3±0.5 and 3.9±1.4 mg/L, respectively. The fold increase in IV & oral M AUC was significantly greater (P≤0.02) after 400mg K (4.2±0.6 & 15±4, respectively) compared to 200mg K (3.4±0.7 & 11±4, respectively) daily. CYP3A5 genotype (*1/*1, *1/*3; n=7 vs. *3/*3; n=8) did not significantly alter the extent of inhibition observed after K dosing (P>0.05). Conclusions The extent of CYP3A inhibition by K is dose dependent with significantly greater effect by 400mg compared to 200mg K dosing. Grant support FDT‐001756 from FDA and M01‐RR00750 from NIH. Clinical Pharmacology & Therapeutics (2005) 77 , P35–P35; doi: 10.1016/j.clpt.2004.12.025