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Methods and strategies for assessing uncontrolled drug–drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group

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Abstract

The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.

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Acknowledgments

The ISOP Working Group would like to thank the ISOP Standards and Best Practices Committee for their thoughtful comments: Nidal al-Huniti, Brian Corrigan, Thomas Dumortier, Gerard Flesch, Daniele Ouellet, and Liping Zhang.

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    Authors and Affiliations

    1. Astellas, 1 Astellas Way, Northbrook, IL, 60062, USA

      Peter L. Bonate

    2. Merck and Co. Inc., 351 N Sumneytown Pike, North Wales, PA, 19454, USA

      Malidi Ahamadi

    3. Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

      Nageshwar Budha

    4. Eli Lilly and Company|Chorus, Lilly Corporate Center, Indianapolis, IN, 46285, USA

      Amparo de la Peña

    5. U.S. Food and Drug Administration, 10903 New Hampshire Ave., Bldg 51, Room 3154, Silver Spring, MD, 20993, USA

      Justin C. Earp

    6. Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936, USA

      Ying Hong

    7. Uppsala University, Box 591, 75124, Uppsala, Sweden

      Mats O. Karlsson

    8. Boehringer Ingelheim Pharmaceutical Inc., 900 Ridgebury Road, Ridgefield, CT, 06877, USA

      Patanjali Ravva

    9. Pfizer, 10646 Science Center Dr. CB10 Office 2448, San Diego, CA, 92121, USA

      Ana Ruiz-Garcia

    10. Parexel International, Inc., 2520 Meridian Parkway, Durham, NC, 27713, USA

      Herbert Struemper

    11. Occams Coöperatie U.A., Malandolaan 10, 1187 HE, Amstelveen, The Netherlands

      Janet R. Wade

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    Correspondence to Peter L. Bonate or Justin C. Earp.

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    All authors contributed equally but are reported in alphabetical order.

    The views and opinions expressed herein by the author Justin Earp, a FDA employee, should not be construed to represent FDA views or policies.

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    Bonate, P.L., Ahamadi, M., Budha, N. et al. Methods and strategies for assessing uncontrolled drug–drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group. J Pharmacokinet Pharmacodyn 43, 123–135 (2016). https://doi.org/10.1007/s10928-016-9464-2

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