Clinical pharmacokinetics · 2023
CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.
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Muhareb Amin, Blank Antje, Meid Andreas D, Foerster Kathrin I, Stoll Felicitas, Burhenne Jürgen, Haefeli Walter E, Mikus Gerd
Аннотация
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 (CLVRZ).
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 (CLMDZ 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CLOMZ 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CLMDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CLOMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CLMDZ was linearly correlated with CLVRZ (slope 1.458; adjusted R2 0.528) as was CLOMZ (slope 0.807; adjusted R2 0.898). Multiple linear regression resulted in an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ using data during voriconazole treatment and an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ + voriconazole dose, using baseline data for CLMDZ and CLOMZ.
CONCLUSION: Microdosed midazolam and omeprazole accurately described and predicted total CLVRZ TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.
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 (CLMDZ 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CLOMZ 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CLMDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CLOMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CLMDZ was linearly correlated with CLVRZ (slope 1.458; adjusted R2 0.528) as was CLOMZ (slope 0.807; adjusted R2 0.898). Multiple linear regression resulted in an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ using data during voriconazole treatment and an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ + voriconazole dose, using baseline data for CLMDZ and CLOMZ.
CONCLUSION: Microdosed midazolam and omeprazole accurately described and predicted total CLVRZ TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.