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. 2020 Jan 25.
doi: 10.1111/cts.12750. Online ahead of print.

In Vitro-to-In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018

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In Vitro-to-In Vivo Extrapolation of Transporter Inhibition Data for Drugs Approved by the US Food and Drug Administration in 2018

Jingjing Yu et al. Clin Transl Sci. .

Abstract

A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro-to-in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P-gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti-infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration-time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically-based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94-1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.

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References

    1. Lee, S.-C. et al. Evaluation of transporters in drug development: current status and contemporary issues. Adv. Drug Deliv. Rev. 116, 100-118 (2017).
    1. FDA’s draft guidance for industry: In Vitro metabolism- and transporter-mediated drug-drug interaction studies (in vitro DDI guidance) (October 2017) <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-metabolism-and-transporter-mediated-drug-drug-interaction-studies-guidance-industry>. Accessed September 18, 2019.
    1. US Food and Drug Administration’s (FDA’s) draft guidance for industry: clinical drug interaction studies-study design, data analysis, and clinical implications (clinical DDI guidance) (October 2017) <https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-study-design-data-analysis-and-clinical-implications-guidance>. Accessed September 18, 2019.
    1. EMA’s Guideline on the Investigation of Drug Interactions (21 June 2012) <https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf>. Accessed September 18, 2019.
    1. MHLW’s guideline on drug interaction for drug development and appropriate provision of information (February 8, 2019) <https://www.mhlw.go.jp/web/t_doc?dataId=00tc3525&dataType=1>. Accessed September 18, 2019.

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