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Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical Considerations

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Abstract

Mathematical modeling has been an important tool in pharmaceutical research for 50 + years and there is increased emphasis over the last decade on using modeling to improve the efficiency and effectiveness of drug development. In an earlier commentary, we applied a multiscale model linking 6 scales (whole body, tumor, vasculature, cell, spatial location, time), together with literature data on nanoparticle and tumor properties, to demonstrate the effects of nanoparticle particles on systemic disposition. The current commentary used a 4-scale model (cell membrane, intracellular organelles, spatial location, time) together with literature data on the intracellular processing of membrane receptors and transporters to demonstrate disruption of transporter homeostasis can lead to drug-drug interaction (DDI) between victim drug (VD) and perpetrator drug (PD), including changes in the area-under-concentration–time-curve of VD in cells that are considered significant by the US Food and Drug Administration (FDA). The model comprised 3 computational components: (a) intracellular transporter homeostasis, (b) pharmacokinetics of extracellular and intracellular VD/PD concentrations, and (c) pharmacodynamics of PD-induced stimulation or inhibition of an intracellular kinetic process. Model-based simulations showed that (a) among the five major endocytic processes, perturbation of transporter internalization or recycling led to the highest incidence and most extensive DDI, with minor DDI for perturbing transporter synthesis and early-to-late endosome and no DDI for perturbing transporter degradation and (b) three experimental conditions (spatial transporter distribution in cells, VD/PD co-incubation time, extracellular PD concentrations) were determinants of DDI detection. We propose modeling is a useful tool for hypothesis generation and for designing experiments to identify potential DDI; its application further aligns with the model-informed drug development paradigm advocated by FDA.

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Funding

Supported in part by research grants from NIH (R01CA163015, R01EB015253) and FDA (20919IPAAU, 20919IPAWIENTJES), the Mosier Endowed Chair in Pharmaceutical Sciences at University of Oklahoma Health Sciences Center, and the Chair in Systems Pharmacology at Taipei Medical University.

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Authors and Affiliations

  1. Institute of Quantitative Systems Pharmacology, Carlsbad, California, 92008, USA

    Roberto A. Abbiati, M. Guillaume Wientjes & Jessie L.-S. Au

  2. Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma, 73117, USA

    Roberto A. Abbiati & Jessie L.-S. Au

  3. Optimum Therapeutics LLC, 1815 Aston Ave, Suite 107, Carlsbad, California, 92008, USA

    M. Guillaume Wientjes & Jessie L.-S. Au

  4. Taipei Medical University, Taipei, Taiwan, Republic of China

    Jessie L.-S. Au

Authors
  1. Roberto A. Abbiati
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  2. M. Guillaume Wientjes
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  3. Jessie L.-S. Au
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Contributions

J.L.-S.A. designed the scientific approach, contributed to the interpretation of simulation results, and wrote the manuscript. R.A.A. and M.G.W. formalized and implemented the model, executed simulations, contributed to the interpretation of simulation results, and contributed to manuscript writing.

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Correspondence to Jessie L.-S. Au.

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Abbiati, R.A., Wientjes, M.G. & Au, J.LS. Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical Considerations. AAPS J 23, 102 (2021). https://doi.org/10.1208/s12248-021-00635-4

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  • DOI: https://doi.org/10.1208/s12248-021-00635-4

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