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Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial

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Abstract

Therapeutic responses of most drugs are initiated by the rate and degree of binding to their receptors or targets. The law of mass action describes the rate of drug-receptor complex association (kon) and dissociation (koff) where the ratio koff/kon is the equilibrium dissociation constant (Kd). Drugs with slow reversible binding (SRB) often demonstrate delayed onset and prolonged pharmacodynamic effects. This report reviews evidence for drugs with SRB features, describes previous pharmacokinetic/pharmacodynamic (PK/PD) modeling efforts of several such drugs, provides a tutorial on the mathematics and properties of SRB models, demonstrates applications of SRB models to additional compounds, and compares PK/PD fittings of SRB with other mechanistic models. We identified and summarized 52 drugs with in vitro-confirmed SRB from a PubMed literature search. Simulations with a SRB model and observed PK/PD profiles showed delayed and prolonged responses and that increasing doses/kon or decreasing koff led to greater expected maximum effects and a longer duration of effects. Recession slopes for return of responses to baseline after single doses were nearly linear with an inflection point that approaches a limiting value at larger doses. The SRB model newly captured literature data for the antihypertensive effects of candesartan and antiallergic effects of noberastine. Their PD profiles could also be fitted with indirect response and biophase models with minimal differences. The applicability of SRB models is probably commonplace, but underappreciated, owing to the need for in vitro confirmation of binding kinetics and the similarity of PK/PD profiles to models with other mechanistic determinants.

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Acknowledgements

Supported by a Fellowship for TR from GlaxoSmithKline and by NIH Grant R35-GM131800 for WJJ.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, 370 Pharmacy Building, Buffalo, NY, 14214-8033, USA

    Tianjing Ren, Wojciech Krzyzanski & William J. Jusko

  2. Novartis Institutes for BioMedical Research, Cambridge, MA, 02139, USA

    Xu Zhu

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA

    Natalie M. Jusko

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  1. Tianjing Ren
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  2. Xu Zhu
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  3. Natalie M. Jusko
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  4. Wojciech Krzyzanski
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  5. William J. Jusko
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Contributions

Contributed to the study conception and design TR, XZ, WJJ; Conducted literature review: TR, XZ; Performed data analysis: TR, XZ, NMJ, WK; Wrote or contributed to the writing of the manuscript: TR, XZ, WK, WJJ.

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Correspondence to William J. Jusko.

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Ren, T., Zhu, X., Jusko, N.M. et al. Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial. J Pharmacokinet Pharmacodyn 49, 493–510 (2022). https://doi.org/10.1007/s10928-022-09822-y

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