A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates

Cole, Susan; Kerwash, Essam; Andersson, Anita

doi:10.1016/j.dmpk.2019.11.005

Cited by 18 publications

(18 citation statements)

References 10 publications

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“… 1 , 4 Thereafter, the qualification dataset described herein can be used to support untested DDI scenarios involving moderate or weak inhibitors of the relevant CYP enzyme as has typically been the case. 4 , 17 …”

Section: Discussionmentioning

confidence: 99%

Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Kilford

Chen

Crewe

et al. 2022

CPT Pharmacom & Syst Pharma

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Physiologically‐based pharmacokinetic (PBPK) modeling is being increasingly used in drug development to avoid unnecessary clinical drug–drug interaction (DDI) studies and inform drug labels. Thus, regulatory agencies are recommending, or indeed requesting, more rigorous demonstration of the prediction accuracy of PBPK platforms in the area of their intended use. We describe a framework for qualification of the Simcyp Simulator with respect to competitive and mechanism‐based inhibition (MBI) of CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. Initially, a DDI matrix, consisting of a range of weak, moderate, and strong inhibitors and substrates with varying fraction metabolized by specific CYP enzymes that were susceptible to different degrees of inhibition, were identified. Simulations were run with 123 clinical DDI studies involving competitive inhibition and 78 clinical DDI studies involving MBI. For competitive inhibition, the overall prediction accuracy was good with an average fold error (AFE) of 0.91 and 0.92 for changes in the maximum plasma concentration (C max ) and area under the plasma concentration (AUC) time profile, respectively, as a consequence of the DDI. For MBI, an AFE of 1.03 was determined for both C max and AUC. The prediction accuracy was generally comparable across all CYP enzymes, irrespective of the isozyme and mechanism of inhibition. These findings provide confidence in application of the Simcyp Simulator (V19 R1) for assessment of the DDI potential of drugs in development either as inhibitors or victim drugs of CYP‐mediated interactions. The approach described herein and the identified DDI matrix can be used to qualify subsequent versions of the platform.

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Section: Discussionmentioning

confidence: 99%

Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Kilford

Chen

Crewe

et al. 2022

CPT Pharmacom & Syst Pharma

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“…Induction of intestinal ABCB1 has been suggested to considerably decrease the bioavailability of drugs after oral administration ( Elmeliegy et al, 2020 ). Therefore, according to the drug interaction guidelines, a drug’s potency to induce drug-metabolizing enzymes and transporters at the mRNA level should be investigated before drugs are commercially launched ( Cole et al, 2020 ). Not only ABCB1 can be strongly induced in enterocytes but also CYP3A4 , mainly via the PXR pathway ( Cerveny et al, 2007 ; van de Kerkhof et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices

et al. 2021

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P-glycoprotein (ABCB1), an ATP-binding cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug–drug interactions. Drug-mediated induction of intestinal ABCB1 is a clinically relevant phenomenon associated with significantly decreased drug bioavailability. Currently, there are no well-established human models for evaluating its induction, so drug regulatory authorities provide no recommendations for in vitro/ex vivo testing drugs’ ABCB1-inducing activity. Human precision-cut intestinal slices (hPCISs) contain cells in their natural environment and express physiological levels of nuclear factors required for ABCB1 induction. We found that hPCISs incubated in William’s Medium E for 48 h maintained intact morphology, ATP content, and ABCB1 efflux activity. Here, we asked whether rifampicin (a model ligand of pregnane X receptor, PXR), at 30 μM, induces functional expression of ABCB1 in hPCISs over 24- and 48-h incubation (the time to allow complete induction to occur). Rifampicin significantly increased gene expression, protein levels, and efflux activity of ABCB1. Moreover, we described dynamic changes in ABCB1 transcript levels in hPCISs over 48 h incubation. We also observed that peaks of induction are achieved among donors at different times, and the extent of ABCB1 gene induction is proportional to PXR mRNA levels in the intestine. In conclusion, we showed that hPCISs incubated in conditions comparable to those used for inhibition studies can be used to evaluate drugs’ ABCB1-inducing potency in the human intestine. Thus, hPCISs may be valuable experimental tools that can be prospectively used in complex experimental evaluation of drug–drug interactions.

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“…The authors analyzed 74 CYP3A4‐mediated DDI studies with a GMFE for AUCR of approximately 1.5. A recently published summary of the current drug interaction guidance from the EMA contained an example of a platform qualification with the purpose to predict time‐dependent inhibition (i.e., mechanism‐based inactivation) of CYP3A4, which wasfinally accepted by the EMA 33 . This analysis included 22 studies of the inhibitors diltiazem, erythromycin, fluoxetine, and ritonavir and showed a GMFE for AUCR of approximately 1.4.…”

Section: Discussionmentioning

confidence: 99%

A generic framework for the physiologically‐based pharmacokinetic platform qualification of PK‐Sim and its application to predicting cytochrome P450 3A4–mediated drug–drug interactions

Frechen

Solodenko

Wendl

et al. 2021

CPT Pharmacom & Syst Pharma

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The success of applications of physiologically‐based pharmacokinetic (PBPK) modeling in drug development and drug labeling has triggered regulatory agencies to demand rigorous demonstration of the predictive capability of the specific PBPK platform for a particular intended application purpose. The effort needed to comply with such qualification requirements exceeds the costs for any individual PBPK application. Because changes or updates of a PBPK platform would require (re‐)qualification, a reliable and efficient generic qualification framework is needed. We describe the development and implementation of an agile and sustainable technical framework for automatic PBPK platform (re‐)qualification of PK‐Sim® embedded in the open source and open science GitHub landscape of Open Systems Pharmacology. The qualification approach enables the efficient assessment of all aspects relevant to the qualification of a particular purpose and provides transparency and traceability for all stakeholders. As a showcase example for the power and versatility of the qualification framework, we present the qualification of PK‐Sim® for the intended purpose of predicting cytochrome P450 3A4 (CYP3A4)–mediated drug–drug interactions (DDIs). Several perpetrator PBPK models featuring various degrees of CYP3A4 modulation and different types of mechanisms (competitive inhibition, mechanism‐based inactivation, and induction) were coupled with a set of PBPK models of sensitive CYP3A4 victim drugs. Simulations were compared to a comprehensive data set of 135 observations from published clinical DDI studies. The platform's overall predictive performance showed reasonable accuracy and precision (geometric mean fold error of 1.4 for both area under the plasma concentration‐time curve ratios and peak plasma concentration ratios with/without perpetrator) and suggests that PK‐Sim® can be applied to quantitatively assess CYP3A4‐mediated DDI in clinically untested scenarios.

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A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates

Cited by 18 publications

References 10 publications

Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Prediction of CYP‐mediated DDIs involving inhibition: Approaches to address the requirements for system qualification of the Simcyp Simulator

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices

A generic framework for the physiologically‐based pharmacokinetic platform qualification of PK‐Sim and its application to predicting cytochrome P450 3A4–mediated drug–drug interactions

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