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To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

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Abstract

Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

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Acknowledgments

We thank our colleagues Dr. Joost Westerhout for helping to collect the in vitro input data to the prediction tool from public literature and Dr. Esther van Duijn for critically reviewing the manuscript.

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  1. Maria L. H. Vlaming

    Present address: Pluriomics B.V., Leiden, The Netherlands

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  1. TNO, Utrechtseweg 48, 3704 HE, Zeist, The Netherlands

    Sieto Bosgra, Maria L. H. Vlaming & Wouter H. J. Vaes

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Correspondence to Sieto Bosgra.

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The authors did not receive any funding for writing this manuscript. S.B. and W.H.J.V. work, and M.L.H.V. formerly worked, for TNO, a not-for-profit research organization that uses accelerator mass spectrometry in both research and fee-for-service projects.

Appendix

Appendix

Box 1 Decision tree for guidance on dose proportionality between microdose and therapeutic dose pharmacokinetics. The decision tree evaluates any of six potential causes for concern that may have been identified in the preclinical phase. The required input is given between brackets. Concentrations and related constants are in molar
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Bosgra, S., Vlaming, M.L.H. & Vaes, W.H.J. To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics. Clin Pharmacokinet 55, 1–15 (2016). https://doi.org/10.1007/s40262-015-0308-9

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