Quantifying the dynamics of the modulatory effect of CYP3A perpetrators on hepatic CYP3A activity using a nonlinear mixed-effects model of microdosed midazolam and its metabolite 1-hydroxymidazolam
Yomna Nassar (1,2), Gerd Mikus (1,3), Wilhelm Huisinga (4), Robin Michelet (1), and Charlotte Kloft (1)
(1) Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Graduate Research Training program PharMetrX, Germany, (3) Department of Clinical Pharmacology and Pharmacoepidemiology University Hospital Heidelberg, Heidelberg, Germany, (4) Institute of Mathematics, University of Potsdam, Germany
Introduction: Cytochrome (CYP) 3A, the most abundant subfamily of CYP450 enzymes, is responsible for the metabolism of ~50% of marketed drugs. It is expressed in the liver and small intestine. Concomitant medications that modulate CYP3A activity (perpetrators) can profoundly alter the exposure of CYP3A substrates [1]. Usually, the maximum effects of perpetrators are reported but not the dynamics. To quantify the extent of CYP3A modulation over time in response to these perpetrators, the CL of the CYP3A specific drug midazolam (MDZ), a short acting sedative and hypnotic agent in therapeutic dose [2] can be used. Following non-pharmacological microgram i.v. dosing, the in vivo activity of “hepatic” CYP3A can be reliably quantified [3].
The objective of this work was to develop an NLME model of MDZ and its metabolite, 1-hydroxymidazolam (OH_MDZ) to quantify the modulatory impact of different CYP3A perpetrators over time, on hepatic CYP3A activity.
Methods: Twenty-four healthy individuals (IDs) received an i.v. MDZ bolus dose (2.7-6.1 µg) followed by an i.v. infusion (2.0-4.4 µg/h) for a total duration of 10-36 hours to achieve a target concentration of 100 pg/mL (EudraCT No: 2013-004869-14). IDs were divided into 4 groups. Within each group, 2 IDs received MDZ+placebo and 4 IDs received MDZ+perpetrator drug; either a CYP3A activator: efavirenz, inducer: rifampicin; or a CYP3A inhibitor: p.o. or i.v. voriconazole (VRC), each administered 2 h after start of MDZ infusion. A total of 1858 observations [range: 36-40 observations/ID/analyte] were equally divided between MDZ and OH_MDZ. Plasma MDZ and OH_MDZ were quantified by a validated LC-MS/MS method [3].
The model was developed using NONMEM®7.4.3 [4] and PsN 4.8.1 [5] with FOCE+I method. The fraction of MDZ metabolised by CYP3A was fixed to 0.92 [6]. To describe the dynamics of CYP3A modulation across time, each study group was divided into discrete time bins, and perpetrator drug effect on CYP3A activity was quantified for its change on MDZ CL compared to the placebo group, per bin, along the sampling duration of MDZ.
Model adequacy was assessed through plausibility and precision of parameter estimates, standard GOF plots, and ΔOFV. Model evaluation was performed using VPC (n = 1000) and sampling importance resampling (SIR).
Results: The PK of MDZ and OH_MDZ following an i.v. bolus/infusion was best described using a 1-compartment model with linear elimination for each analyte. Parameter estimates were similar to values derived from oral and i.v bolus doses [7,8,9]. Total MDZ CL (CLMDZ) was 43.9 L/h; consisting of CYP3A- and non-CYP3A-mediated CL (40.4 L/h and 3.51 L/h, respectively). VMDZ was 56.7 L. Whereas for OH_MDZ, total CLOH_MDZ and VOH_MDZ, were 264 L/h and 300 L, respectively. Interindividual variability was 21.9%, 29.9%, 42.0% and 39.9% CV for CLMDZ, VMDZ, CLOH_MDZ and VOH_MDZ, respectively. Proportional residual variability was quantified to be 12.6% CV for MDZ and 22.6% CV for OH_MDZ.
SIR-reported RSEs (4.37%–43.5%) indicated precise parameter estimates. The VPC captured the observed concentrations of the 10th, 50th, and 90th percentiles for both MDZ and OH_MDZ except for an underprediction in the 50th percentile of the placebo IDs in the rifampicin group at the later time points.
Quantification of perpetrator effects across the bins captured the changes in MDZ CL relative to time, as a result of CYP3A modulation. For efavirenz, CYP3A activation increased gradually, reaching a maximum effect at 2-3 h (relative change in CL (RelCL) +59.2%). For rifampicin, first induction was observed between 28-30 h (i.e. 2-4 h after administration of a 2nd dose) (RelCL +46.8%). For p.o. and i.v. VRC, the inhibitory effect was stable for the first 4 h, then a 2-fold drop occurred 4-6 h post VRC administration and continued reaching the maximum inhibitory effect (RelCL -70.6% and -61.1%, respectively).
Conclusion: Changes in CL beyond 80%-125% (<35.1 L/h and >54.9 L/h), identify and suggest monitoring time for a significant modulatory effect. These changes occurred by administration of the perpetrator after 2 h (efavirenz), 28 h (rifampicin), immediately (p.o. VRC) and 4 h (i.v. VRC). Therefore, knowledge of the dynamic profile of each perpetrator aids the dose adjustment of concomitant CYP3A substrates relative to the time of administration. Additionally, the model can be applied to screen for perpetrators in drug development and to support the design of future DDI studies.
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