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Research ArticleMinireviews

What Can Be Learned from Recent New Drug Applications? A Systematic Review of Drug Interaction Data for Drugs Approved by the US FDA in 2015

Jingjing Yu, Zhu Zhou, Katie H. Owens, Tasha K. Ritchie and Isabelle Ragueneau-Majlessi
Drug Metabolism and Disposition January 2017, 45 (1) 86-108; DOI: https://doi.org/10.1124/dmd.116.073411
Jingjing Yu
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Zhu Zhou
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Katie H. Owens
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Tasha K. Ritchie
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Isabelle Ragueneau-Majlessi
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Abstract

As a follow up to previous reviews, the aim of the present analysis was to systematically examine all drug metabolism, transport, pharmacokinetics (PK), and drug-drug interaction (DDI) data available in the 33 new drug applications (NDAs) approved by the Food and Drug Administration (FDA) in 2015, using the University of Washington Drug Interaction Database, and to highlight the significant findings. In vitro, a majority of the new molecular entities (NMEs) were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, 95 clinical DDI studies displayed positive PK interactions, with an area under the curve (AUC) ratio ≥ 1.25 for inhibition or ≤ 0.8 for induction. When NMEs were considered as victim drugs, 21 NMEs had at least one positive clinical DDI, with three NMEs shown to be sensitive substrates of CYP3A (AUC ratio ≥ 5 when coadministered with strong inhibitors): cobimetinib, isavuconazole (the active metabolite of prodrug isavuconazonium sulfate), and ivabradine. As perpetrators, nine NMEs showed positive inhibition and three NMEs showed positive induction, with some of these interactions involving both enzymes and transporters. The most significant changes for inhibition and induction were observed with rolapitant, a moderate inhibitor of CYP2D6 and lumacaftor, a strong inducer of CYP3A. Physiologically based pharmacokinetics simulations and pharmacogenetics studies were used for six and eight NMEs, respectively, to inform dosing recommendations. The effects of hepatic or renal impairment on the drugs’ PK were also evaluated to support drug administration in these specific populations.

Footnotes

    • Received September 1, 2016.
    • Accepted November 2, 2016.
  • ↵1 Current affiliation: Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA.

  • dx.doi.org/10.1124/dmd.116.073411.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (1)
Drug Metabolism and Disposition
Vol. 45, Issue 1
1 Jan 2017
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Research ArticleMinireviews

A review of drug disposition and DDIs in 2015 NDAs

Jingjing Yu, Zhu Zhou, Katie H. Owens, Tasha K. Ritchie and Isabelle Ragueneau-Majlessi
Drug Metabolism and Disposition January 1, 2017, 45 (1) 86-108; DOI: https://doi.org/10.1124/dmd.116.073411

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Research ArticleMinireviews

A review of drug disposition and DDIs in 2015 NDAs

Jingjing Yu, Zhu Zhou, Katie H. Owens, Tasha K. Ritchie and Isabelle Ragueneau-Majlessi
Drug Metabolism and Disposition January 1, 2017, 45 (1) 86-108; DOI: https://doi.org/10.1124/dmd.116.073411
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  • Article
    • Abstract
    • Introduction
    • Metabolism and Enzyme-Mediated DDIs
    • Transport and Transporter-Mediated DDIs
    • PGx Studies
    • PBPK Modeling and Simulations
    • Clinically Significant DDIs
    • Hepatic Impairment (HI) and Renal Impairment (RI) Studies
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  • A Decade in the MIST
  • A Review of PK-Based DDIs in 2013–2016 NDAs
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