Dataset Information

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.

SUBMITTER: Muhareb A

PROVIDER: S-EPMC10450012 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Muhareb Amin A Blank Antje A Meid Andreas D AD Foerster Kathrin I KI Stoll Felicitas F Burhenne Jürgen J Haefeli Walter E WE Mikus Gerd G

Clinical pharmacokinetics 20230728 9

<h4>Background and objective</h4>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<sub>VRZ</sub>).<h4>Methods</h4>At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were ...[more]

PMID: 37505445

Similar Datasets

Project description:BackgroundCytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice.ObjectiveWe aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity.MethodsTwenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm.ResultsTime course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively.ConclusionsWe could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.Clinical trial registrationThe trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14).

Dataset Information

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

Background and objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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