Received for publication June 29, 2006.
Revised September 20, 2006.
Accepted for publication September 20, 2006.

Drug Metabolizing Enzyme Inhibition by Ketoconazole Does Not Reduce Interindividual Variability of CYP3A Activity as Measured by Oral Midazolam

Abstract

Variable interindividual expression of cytochrome P450 (CYP) 3A presents a challenge in dosing drugs. Potent inhibitors of CYP3A such as ketoconazole have been explored to reduce the clearance of CYP3A substrates, thereby resulting in smaller dose requirements; however the impact of CYP3A inhibition on interindividual variability has not been well characterized. Our objective was to examine the effect of ketoconazole inhibition on CYP3A metabolic variability as measured by the CYP3A biomarker oral midazolam. A single dose of midazolam (0.075 mg/kg) was administered to 19 healthy Caucasian adults (38.7±8.8 yrs, 9M/10F) at baseline and concurrently with ketoconazole (400 mg daily for 10 days) on day 6 or 9 of ketoconazole. Plasma samples were collected over 6-30 hours. A paired t-test and percent coefficient of variation (CV%) were used to evaluate differences in midazolam clearance and interindividual variability during both phases. Monte Carlo simulation was performed to determine probability distribution of area under the concentration-time curves (AUCs). Midazolam apparent oral clearance (CL/F) decreased by 89% (p<0.0001) during inhibition. Cmax increased from 23 ng/mL (95%CI 19-29 ng/mL) to 55 ng/mL (95%CI 46-66 ng/mL), p<0.0001. CV% increased from 41% to 58% from baseline to ketoconazole inhibition. AUC [median; range] were (0.20 mg•min/mL; 0.05 - 0.81 mg•min/mL) and (1.94 mg•min/mL; 0.25 - 25.4 mg•min/mL) at baseline and inhibition phase, with CV% of 41% and 61%, respectively. Ketoconazole decreased CYP3A activity but did not reduce interindividual variability. Use of a CYP3A inhibitor to standardize dosing of CYP3A substrates may not be feasible in clinical practice.

Key words: CYP inhibition, CYP3A, enzyme inhibitors, human CYP enzymes, in vivo probes, inhibition, Monte Carlo simulations, imidazole drugs

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