The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline

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Abstract

The National Institutes of Health has partnered with the US Food and Drug Administration and the Defense Advanced Research Projects Agency to accelerate the development of human microphysiological systems (MPS) that address challenges faced in predictive toxicity assessment and efficacy analysis of new molecular entities during the preclinical phase of drug development. Use of human MPS could provide better models for predicting the efficacy of new molecular entities in clinical trials. It is also anticipated that improvements in predicting drug toxicities early in the drug development process through the use of MPS or human organs-on-a-chip will decrease the need to withdraw new therapies from the market and minimize or eliminate deaths due to unidentified drug toxicities.

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Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.

Marcella Martignoni, Geny Groothuis, Ruben de Kanter (2006)

Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.

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Timing of new black box warnings and withdrawals for prescription medications.

Karen Lasser (2002)

Recently approved drugs may be more likely to have unrecognized adverse drug reactions (ADRs) than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs. To determine the frequency and timing of discovery of new ADRs described in black box warnings or necessitating withdrawal of the drug from the market. Examination of the Physicians' Desk Reference for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning). Frequency of and time to a new black box warning or drug withdrawal. A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%. Eighty-one major changes to drug labeling in the Physicians' Desk Reference occurred including the addition of 1 or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier analyses, half of these changes occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years. Serious ADRs commonly emerge after Food and Drug Administration approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years.

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Coumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment

B.G Lake (1999)

The metabolism, toxicity and results of tests for carcinogenicity have been reviewed with respect to the safety for humans of coumarin present in foodstuffs and from fragrance use in cosmetic products. Coumarin is a natural product which exhibits marked species differences in both metabolism and toxicity. The majority of tests for mutagenic and genotoxic potential suggest that coumarin is not a genotoxic agent. The target organs for toxicity and carcinogenicity in the rat and mouse are primarily the liver and lung. Moreover, the dose-response relationships for coumarin-induced toxicity and carcinogenicity are non-linear, with tumour formation only being observed at high doses which are associated with hepatic and pulmonary toxicity. Other species, including the Syrian hamster, are seemingly resistant to coumarin-induced toxicity. There are marked differences in coumarin metabolism between susceptible rodent species and other species including humans. It appears that the 7-hydroxylation pathway of coumarin metabolism, the major pathway in most human subjects but only a minor pathway in the rat and mouse, is a detoxification pathway. In contrast, the major route of coumarin metabolism in the rat and mouse is by a 3,4-epoxidation pathway resulting in the formation of toxic metabolites. The maximum daily human exposure to coumarin from dietary sources for a 60-kg consumer has been estimated to be 0.02 mg/kg/day. From fragrance use in cosmetic products, coumarin exposure has been estimated to be 0.04 mg/kg/day. The total daily human exposure from dietary sources together with fragrance use in cosmetic products is thus 0.06 mg/kg/day. No adverse effects of coumarin have been reported in susceptible species in response to doses which are more than 100 times the maximum human daily intake. The mechanism of coumarin-induced tumour formation in rodents is associated with metabolism-mediated, toxicity and it is concluded that exposure to coumarin from food and/or cosmetic products poses no health risk to humans.

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Author and article information

Contributors

Margaret L Sutherland

Kristin M Fabre

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central

ISSN (Electronic): 1757-6512

Publication date Collection: 2013

Publication date (Electronic): 20 December 2013

Publication date PMC-release: 20 December 2014

Volume: 4

Issue: Suppl 1

Page: I1

Affiliations

[1 ]National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Blvd., Bethesda, MD 20892, USA

[2 ]National Center for Advancing Translational Sciences, National Institutes of Health, 6701 Democracy Blvd., Bethesda MD 20892, USA

Article

Publisher ID: scrt361

DOI: 10.1186/scrt361

PMC ID: 4029183

PubMed ID: 24565163

SO-VID: 5de941e5-19a0-4a99-ad66-47b83d450f70

Copyright © Copyright © 2013 The article is a work of the United States Government; Title 17 U.S.C 105 provides that copyright protection is not available for any work of the United States government in the United States; licensee BioMed Central Ltd.

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This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline

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Most cited references 10

Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.

Timing of new black box warnings and withdrawals for prescription medications.

Coumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment

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