Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach

Fuhr, Laura Maria; Marok, Fatima Zahra; Hanke, Nina; Selzer, Dominik; Lehr, Thorsten

doi:10.3390/pharmaceutics13020270

Cited by 39 publications

(34 citation statements)

References 76 publications

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“…Besides the induction mechanism differences, carbamazepine was used most in clinical DDI studies after rifampicin for assessment of CYP3A induction, followed by phenytoin, with two reports of lumacaftor DDI studies with ivacaftor and itraconazole as CYP3A substrates. With the most abundant clinical data among the three alternatives (Table 2) and advances in PBPK modeling for DDI predictions, carbamazepine could be an immediate alternative to rifampicin 74 . However, carbamazepine is a narrow therapeutic index (NTI) drug and requires dose titration.…”

Section: Alternative Strong Inducers Of Cyp3amentioning

confidence: 99%

“…With the most abundant clinical data among the three alternatives (Table 2 ) and advances in PBPK modeling for DDI predictions, carbamazepine could be an immediate alternative to rifampicin. 74 However, carbamazepine is a narrow therapeutic index (NTI) drug and requires dose titration. With lesser clinical drug interaction studies, phenytoin ranks third in line as an index inducer to conduct CYP3A‐mediated drug interaction studies.…”

Section: Alternative Strong Inducers Of Cyp3amentioning

confidence: 99%

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Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Bolleddula

Gopalakrishnan

et al. 2022

Clinical Translational Sci

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N‐Nitrosamine (NA) impurities are considered genotoxic and have gained attention due to the recall of several marketed drug products associated with higher‐than‐permitted limits of these impurities. Rifampicin is an index inducer of multiple cytochrome P450s (CYPs) including CYP2B6, 2C8, 2C9, 2C19, and 3A4/5 and an inhibitor of OATP1B transporters (single dose). Hence, rifampicin is used extensively in clinical studies to assess drug–drug interactions (DDIs). Despite NA impurities being reported in rifampicin and rifapentine above the acceptable limits, these critical anti‐infective drugs are available for therapeutic use considering their benefit–risk profile. Reports of NA impurities in rifampicin products have created uncertainty around using rifampicin in clinical DDI studies, especially in healthy volunteers. Hence, a systematic investigation through a literature search was performed to determine possible alternative index inducer(s) to rifampicin. The available strong CYP3A inducers were selected from the University of Washington DDI Database and their in vivo DDI potential assessed using the data from clinical DDI studies with sensitive CYP3A substrates. To propose potential alternative CYP3A inducers, factors including lack of genotoxic potential, adequate safety, feasibility of multiple dose administration to healthy volunteers, and robust in vivo evidence of induction of CYP3A were considered. Based on the qualifying criteria, carbamazepine, phenytoin, and lumacaftor were identified to be the most promising alternatives to rifampicin for conducting CYP3A induction DDI studies. Strengths and limitations of the proposed alternative CYP3A inducers, the magnitude of in vivo CYP3A induction, appropriate study designs for each alternative inducer, and future perspectives are presented in this paper.

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Section: Alternative Strong Inducers Of Cyp3amentioning

confidence: 99%

Section: Alternative Strong Inducers Of Cyp3amentioning

confidence: 99%

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Bolleddula

Gopalakrishnan

et al. 2022

Clinical Translational Sci

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“…The model adequately describes the CAB RIF DDI plasma concentration time profile and is in good agreement with the observed data. The correct prediction of the impact of the perpetrator drug indicates the correct implementation of the relevant elimination pathways of the victim drug and the right amount of drug eliminated via that pathway [ 55 ]. After a single dose administration, it was not possible to match AUC last values of the control data by only increasing the amount of the single dose, as in that case, C max will also strongly increase, which could have an impact on safety.…”

Section: Discussionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Gerner

Scherf‐Clavel

2021

Pharmaceutics

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Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

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“…The felodipine PBPK model was applied as a CYP3A4 victim drug model to predict DDIs with the CYP3A4 inhibitors erythromycin and itraconazole and the CYP3A4 inducers carbamazepine and phenytoin. For erythromycin [ 30 ], itraconazole [ 31 ], carbamazepine [ 32 ], and phenytoin (unpublished, in-house), we used available PBPK models that have been previously evaluated for DDI predictions as CYP3A4 perpetrator models.…”

Section: Methodsmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic and Pharmacodynamic Model of the CYP3A4 Substrate Felodipine for Drug–Drug Interaction Modeling

et al. 2022

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The antihypertensive felodipine is a calcium channel blocker of the dihydropyridine type, and its pharmacodynamic effect directly correlates with its plasma concentration. As a sensitive substrate of cytochrome P450 (CYP) 3A4 with high first-pass metabolism, felodipine shows low oral bioavailability and is susceptible to drug–drug interactions (DDIs) with CYP3A4 perpetrators. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) parent–metabolite model of felodipine and its metabolite dehydrofelodipine for DDI predictions. The model was developed in PK-Sim® and MoBi® using 49 clinical studies (94 plasma concentration–time profiles in total) that investigated different doses (1–40 mg) of the intravenous and oral administration of felodipine. The final model describes the metabolism of felodipine to dehydrofelodipine by CYP3A4, sufficiently capturing the first-pass metabolism and the subsequent metabolism of dehydrofelodipine by CYP3A4. Diastolic blood pressure and heart rate PD models were included, using an Emax function to describe the felodipine concentration–effect relationship. The model was tested in DDI predictions with itraconazole, erythromycin, carbamazepine, and phenytoin as CYP3A4 perpetrators, with all predicted DDI AUClast and Cmax ratios within two-fold of the observed values. The model will be freely available in the Open Systems Pharmacology model repository and can be applied in DDI predictions as a CYP3A4 victim drug.

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Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach

Cited by 39 publications

References 76 publications

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

A Physiologically Based Pharmacokinetic and Pharmacodynamic Model of the CYP3A4 Substrate Felodipine for Drug–Drug Interaction Modeling

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