CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Clinical pharmacokinetics - 62(2023), 9 vom: 28. Sept., Seite 1305-1314 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Muhareb, Amin [VerfasserIn] |
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| Links: |
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| Themen: |
CYP2C19 protein, human |
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| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 06.09.2023 published: Print-Electronic DRKS: DRKS00022547 Citation Status MEDLINE |
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| doi: |
10.1007/s40262-023-01287-7 |
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| PPN (Katalog-ID): |
NLM360053424 |
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| 245 | 1 | 0 | |a CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults |
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| 500 | |a Date Completed 25.08.2023 | ||
| 500 | |a Date Revised 06.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a DRKS: DRKS00022547 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Blank, Antje |e verfasserin |4 aut | |
| 700 | 1 | |a Meid, Andreas D |e verfasserin |4 aut | |
| 700 | 1 | |a Foerster, Kathrin I |e verfasserin |4 aut | |
| 700 | 1 | |a Stoll, Felicitas |e verfasserin |4 aut | |
| 700 | 1 | |a Burhenne, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Haefeli, Walter E |e verfasserin |4 aut | |
| 700 | 1 | |a Mikus, Gerd |e verfasserin |4 aut | |
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