CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults

Abstract

Background and objective: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL_VRZ).

Methods: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs.

Results: The clearances of midazolam (CL_MDZ 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CL_OMZ 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CL_MDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CL_OMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CL_MDZ was linearly correlated with CL_VRZ (slope 1.458; adjusted R² 0.528) as was CL_OMZ (slope 0.807; adjusted R² 0.898). Multiple linear regression resulted in an adjusted R² of 0.997 for the relationship CL_VRZ ~ log CL_OMZ + log CL_MDZ using data during voriconazole treatment and an adjusted R² of 0.997 for the relationship CL_VRZ ~ log CL_OMZ + log CL_MDZ + voriconazole dose, using baseline data for CL_MDZ and CL_OMZ.

Conclusion: Microdosed midazolam and omeprazole accurately described and predicted total CL_VRZ TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.