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Poster at PAGE 2022: Dose Adaptations for Drug-Gene and Drug-Drug Interactions involving Clopidogrel – A Physiologically based Pharmacokinetic (PBPK) Modeling Approach #388
Introduction: The antiplatelet agent clopidogrel is widely used for the prevention of atherothrombotic events [1]. Clopidogrel's active metabolite (Clo-AM) is primarily formed in two oxidative steps via cytochrome P450 (CYP) 2C19 [2]. Considering different CYP2C19 phenotypes, application of clopidogrel shows considerable variation in Clo-AM exposure [3]. Moreover, clopidogrel is listed by the United States Food and Drug Administration (FDA) as strong clinical index inhibitor of CYP2C8 (specifically its metabolite clopidogrel acyl glucuronide) and weak clinical inhibitor of CYP2B6 [4], acting as mechanism-based inactivator in both cases. To ensure effective therapy of clopidogrel and concurrently administered drugs while maintaining adequate control of adverse events, dose adaptations for drug-gene (DGI) and drug-drug interaction (DDI) scenarios should be thoroughly investigated. Here, physiologically based pharmacokinetic (PBPK) modeling can assist finding optimal dosage regimens, as it allows quantitative prediction of drug pharmacokinetics (PK).
Objectives: Application of a previously developed PBPK model of clopidogrel to perform dose adaptations for
the clopidogrel-CYP2C19 DGI, i.e., for intermediate (IM) and poor metabolizer (PM) phenotypes
CYP2C8 victim drugs repaglinide, pioglitazone, and montelukast during clopidogrel co-administration
Methods: A recently developed whole-body PBPK model of clopidogrel and its four relevant metabolites, developed in PK-Sim® (version 9.1) and applied to predict the CYP2C19 DGI and DDIs with repaglinide, pioglitazone, and montelukast [5], was used for dose optimizations. Regarding clopidogrel, the optimization target was defined as the predicted area under the plasma concentration-time curve (AUC) of Clo-AM for CYP2C19 normal metabolizers (NMs) following a standard 75 mg maintenance dose of clopidogrel. For CYP2C19 IMs and PMs, the clopidogrel dose was gradually increased until the respective Clo-AM AUC matched the target exposure in NMs. Accordingly, a stepwise dose reduction was conducted for the CYP2C8 substrates repaglinide, pioglitazone, and montelukast when co-administered with clopidogrel (DDI) to achieve AUCs equivalent to the AUCs when given alone (Control).
Results: Simulated dose adaptations showed that increases of the initial clopidogrel dose to 200% for IMs of CYP2C19 and 450% for PMs would be required to establish Clo-AM exposures comparable to that of NMs. However, while Clo-AM AUCs could be matched for the different phenotypes, higher clopidogrel doses resulted in a marked increase in clopidogrel exposure (210% and 533% for IMs and PMs, respectively). In comparison, guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC), French National Network of Pharmacogenetics (RNPGx), and Royal Dutch Pharmacists Association – Pharmacogenetics Working Group (DPWG) all recommend substitution of clopidogrel with an alternative drug (i.e., prasugrel or ticagrelor) for IMs and PMs of CYP2C19, with the DPWG guideline additionally stating the possibility of a 200% increase in clopidogrel dose for IMs [6–8]. Regarding the CYP2C8 substrates repaglinide, pioglitazone, and montelukast, dose reductions of 88%, 67%, and 40%, respectively, were necessary when administered concomitantly with clopidogrel to achieve AUC values equivalent to the references. Due to the mechanism-based inactivation, trajectories of the victims showed decreased maximum plasma concentration (Cmax) values and flattened elimination phases compared to the application without clopidogrel. The potential impact of the victims’ altered PK on efficacy and safety cannot be predicted by the current model but should be investigated in further studies.
Conclusions: Dose adaptations were performed using a PBPK model of clopidogrel for CYP2C19 IMs and PMs as well as for the CYP2C8 substrates repaglinide, pioglitazone, and montelukast when administered with clopidogrel as perpetrator. Target Clo-AM exposures could be met for CYP2C19 IMs and PMs by dose adjustments in simulation scenarios. However, pronounced increases in clopidogrel exposure occurred for both IMs and PMs, potentially causing an aggravated risk of adverse events and interactions, supporting the guidelines recommendation for clopidogrel substitution. For the CYP2C8 substrates, the AUCs could be matched to the reference values by dose decreases, while trajectories and PK remained altered.
Helena Leonie Hanae Loer, Denise Türk, Dominik Selzer, and Thorsten Lehr
https://www.page-meeting.org/default.asp?abstract=9999
Introduction: The antiplatelet agent clopidogrel is widely used for the prevention of atherothrombotic events [1]. Clopidogrel's active metabolite (Clo-AM) is primarily formed in two oxidative steps via cytochrome P450 (CYP) 2C19 [2]. Considering different CYP2C19 phenotypes, application of clopidogrel shows considerable variation in Clo-AM exposure [3]. Moreover, clopidogrel is listed by the United States Food and Drug Administration (FDA) as strong clinical index inhibitor of CYP2C8 (specifically its metabolite clopidogrel acyl glucuronide) and weak clinical inhibitor of CYP2B6 [4], acting as mechanism-based inactivator in both cases. To ensure effective therapy of clopidogrel and concurrently administered drugs while maintaining adequate control of adverse events, dose adaptations for drug-gene (DGI) and drug-drug interaction (DDI) scenarios should be thoroughly investigated. Here, physiologically based pharmacokinetic (PBPK) modeling can assist finding optimal dosage regimens, as it allows quantitative prediction of drug pharmacokinetics (PK).
Objectives: Application of a previously developed PBPK model of clopidogrel to perform dose adaptations for
Methods: A recently developed whole-body PBPK model of clopidogrel and its four relevant metabolites, developed in PK-Sim® (version 9.1) and applied to predict the CYP2C19 DGI and DDIs with repaglinide, pioglitazone, and montelukast [5], was used for dose optimizations. Regarding clopidogrel, the optimization target was defined as the predicted area under the plasma concentration-time curve (AUC) of Clo-AM for CYP2C19 normal metabolizers (NMs) following a standard 75 mg maintenance dose of clopidogrel. For CYP2C19 IMs and PMs, the clopidogrel dose was gradually increased until the respective Clo-AM AUC matched the target exposure in NMs. Accordingly, a stepwise dose reduction was conducted for the CYP2C8 substrates repaglinide, pioglitazone, and montelukast when co-administered with clopidogrel (DDI) to achieve AUCs equivalent to the AUCs when given alone (Control).
Results: Simulated dose adaptations showed that increases of the initial clopidogrel dose to 200% for IMs of CYP2C19 and 450% for PMs would be required to establish Clo-AM exposures comparable to that of NMs. However, while Clo-AM AUCs could be matched for the different phenotypes, higher clopidogrel doses resulted in a marked increase in clopidogrel exposure (210% and 533% for IMs and PMs, respectively). In comparison, guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC), French National Network of Pharmacogenetics (RNPGx), and Royal Dutch Pharmacists Association – Pharmacogenetics Working Group (DPWG) all recommend substitution of clopidogrel with an alternative drug (i.e., prasugrel or ticagrelor) for IMs and PMs of CYP2C19, with the DPWG guideline additionally stating the possibility of a 200% increase in clopidogrel dose for IMs [6–8]. Regarding the CYP2C8 substrates repaglinide, pioglitazone, and montelukast, dose reductions of 88%, 67%, and 40%, respectively, were necessary when administered concomitantly with clopidogrel to achieve AUC values equivalent to the references. Due to the mechanism-based inactivation, trajectories of the victims showed decreased maximum plasma concentration (Cmax) values and flattened elimination phases compared to the application without clopidogrel. The potential impact of the victims’ altered PK on efficacy and safety cannot be predicted by the current model but should be investigated in further studies.
Conclusions: Dose adaptations were performed using a PBPK model of clopidogrel for CYP2C19 IMs and PMs as well as for the CYP2C8 substrates repaglinide, pioglitazone, and montelukast when administered with clopidogrel as perpetrator. Target Clo-AM exposures could be met for CYP2C19 IMs and PMs by dose adjustments in simulation scenarios. However, pronounced increases in clopidogrel exposure occurred for both IMs and PMs, potentially causing an aggravated risk of adverse events and interactions, supporting the guidelines recommendation for clopidogrel substitution. For the CYP2C8 substrates, the AUCs could be matched to the reference values by dose decreases, while trajectories and PK remained altered.