A Physiologically-Based Pharmacokinetic (PBPK) Model Network for the Prediction of CYP1A2 and CYP2C19 Drug–Drug–Gene Interactions with Fluvoxamine, Omeprazole, S-mephenytoin, Moclobemide, Tizanidine, Mexiletine, Ethinylestradiol, and Caffeine

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Abstract

Physiologically-based pharmacokinetic (PBPK) modeling is a well-recognized method for quantitatively predicting the effect of intrinsic/extrinsic factors on drug exposure. However, there are only few verified, freely accessible, modifiable, and comprehensive drug–drug interaction (DDI) PBPK models. We developed a qualified whole-body PBPK DDI network for cytochrome P450 (CYP) CYP2C19 and CYP1A2 interactions. Template PBPK models were developed for interactions between fluvoxamine, S-mephenytoin, moclobemide, omeprazole, mexiletine, tizanidine, and ethinylestradiol as the perpetrators or victims. Predicted concentration–time profiles accurately described a validation dataset, including data from patients with genetic polymorphisms, demonstrating that the models characterized the CYP2C19 and CYP1A2 network over the whole range of DDI studies investigated. The models are provided on GitHub (GitHub Inc., San Francisco, CA, USA), expanding the library of publicly available qualified whole-body PBPK models for DDI predictions, and they are thereby available to support potential recommendations for dose adaptations, support labeling, inform the design of clinical DDI trials, and potentially waive those.

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Most cited references 28

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Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

X. Zhao, D Flockhart, Jae-Ho Shin … (2001)

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

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Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective

Mohamad Shebley, Punam Sandhu, Arian Emami Riedmaier … (2018)

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

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Clinical relevance of genetic polymorphisms in the human CYP2C subfamily.

Joyce Goldstein (2001)

The human CYP2Cs are an important subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs. There are four members of the subfamily, CYP2C8, CYP2C9, CYP2C19, and CYP2C18. Of these CYP2C8, CYP2C9, and CYP2C19 are of clinical importance. The CYP2Cs also metabolize some endogenous compounds such as arachidonic acid. Each member of this subfamily has been found to be genetically polymorphic. The most well-known of these polymorphisms is in CYP2C19. Poor metabolizers (PMs) of CYP2C19 represent approximately 3-5% of Caucasians, a similar percentage of African-Americans and 12-100% of Asian groups. The polymorphism affects metabolism of the anticonvulsant agent mephenytoin, proton pump inhibitors such as omeprazole, the anxiolytic agent diazepam, certain antidepressants, and the antimalarial drug proguanil. Toxic effects can occur in PMs exposed to diazepam, and the efficacy of some proton pump inhibitors may be greater in PMs than EMs at low doses of these drugs. A number of mutant alleles exist that can be detected by genetic testing. CYP2C9 metabolizes a wide variety of drugs including the anticoagulant warfarin, antidiabetic agents such as tolbutamide, anticonvulsants such as phenytoin, and nonsteroidal anti-inflammatory drugs. The incidence of functional polymorphisms is much lower, estimated to be 1/250 in Caucasians and lower in Asians. However, the clinical consequences of these rarer polymorphisms can be severe. Severe and life-threatening bleeding episodes have been reported in CYP2C9 PMs exposed to warfarin. Phenytoin has been reported to cause severe toxicity in PMs. New polymorphisms have been discovered in CYP2C8, which metabolizes taxol (paclitaxel). Genetic testing is available for all of the known CYP2C variant alleles.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 08 December 2020

Publication date Collection: December 2020

Volume: 12

Issue: 12

Electronic Location Identifier: 1191

Affiliations

[1 ]SGS-Exprimo, 2800 Mechelen, Belgium; tobias.kanacher@ 123456pharmetheus.com (T.K.); andreas.lindauer@ 123456gmail.com (A.L.); enrica.mezzalana@ 123456pharmetheus.com (E.M.); Ingrid.Michon@ 123456certara.com (I.M.)

[2 ]Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach an der Riß, Germany; celine.veau@ 123456boehringer-ingelheim.com (C.V.); jose_david.gomez_mantilla@ 123456boehringer-ingelheim.com (J.D.G.M.); Valerie.nock@ 123456boehringer-ingelheim.com (V.N.)

Author notes

[* ]Correspondence: angele.fleury@ 123456boehringer-ingelheim.com ; Tel.: +49-7351-54-96020

[†]

Current Address: PPharmetheus, Dag Hammarskjölds Väg 36B, 75237 Uppsala, Sweden.

[‡]

Current Address: Calvagone, 772 Montée de Chalier, 69400 Liergues, France.

[§]

Current Address: Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK.

Article

Publisher ID: pharmaceutics-12-01191

DOI: 10.3390/pharmaceutics12121191

PMC ID: 7764797

PubMed ID: 33302490

SO-VID: 86320c0e-e731-4634-b9bd-d22910f767d0

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

A Physiologically-Based Pharmacokinetic (PBPK) Model Network for the Prediction of CYP1A2 and CYP2C19 Drug–Drug–Gene Interactions with Fluvoxamine, Omeprazole, S-mephenytoin, Moclobemide, Tizanidine, Mexiletine, Ethinylestradiol, and Caffeine

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Most cited references 28

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective

Clinical relevance of genetic polymorphisms in the human CYP2C subfamily.

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