C-06

Dose Dependent Inhibition of Midazolam Elimination by Ketoconazole: Effect of CYP3A5 Genotype

A. Lucksiri¹ , R. Vuppalanchi² , J. K. Hilligoss² , M. A. Hamman² , L. Li² , J. Y. Chien³ , S. M. Huang⁴ , S. Hall² , ¹Purdue University, ²Indiana University, ³Eli Lilly &Co, ⁴OCPB, CDER, FDA

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+16 ug/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.