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CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.
- Source :
- Clinical Pharmacokinetics; Sep2023, Vol. 62 Issue 9, p1305-1314, 10p
- Publication Year :
- 2023
-
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<subscript>VRZ</subscript>). 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<subscript>MDZ</subscript> 790–2790 mL/min at baseline; 248–1316 mL/min during voriconazole) and omeprazole (CL<subscript>OMZ</subscript> 66.4–2710 mL/min at baseline; 30.1–1420 mL/min during voriconazole) were highly variable. CL<subscript>MDZ</subscript> [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CL<subscript>OMZ</subscript> (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CL<subscript>MDZ</subscript> was linearly correlated with CL<subscript>VRZ</subscript> (slope 1.458; adjusted R<superscript>2</superscript> 0.528) as was CL<subscript>OMZ</subscript> (slope 0.807; adjusted R<superscript>2</superscript> 0.898). Multiple linear regression resulted in an adjusted R<superscript>2</superscript> of 0.997 for the relationship CL<subscript>VRZ</subscript> ~ log CL<subscript>OMZ</subscript> + log CL<subscript>MDZ</subscript> using data during voriconazole treatment and an adjusted R<superscript>2</superscript> of 0.997 for the relationship CL<subscript>VRZ</subscript> ~ log CL<subscript>OMZ</subscript> + log CL<subscript>MDZ</subscript> + voriconazole dose, using baseline data for CL<subscript>MDZ</subscript> and CL<subscript>OMZ</subscript>. Conclusion: Microdosed midazolam and omeprazole accurately described and predicted total CL<subscript>VRZ</subscript> Trial Registration: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03125963
- Volume :
- 62
- Issue :
- 9
- Database :
- Complementary Index
- Journal :
- Clinical Pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 170398827
- Full Text :
- https://doi.org/10.1007/s40262-023-01287-7