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Physiologically-Based Pharmacokinetic Models of CYP2D6 Substrate and Inhibitors Nebivolol, Cinacalcet and Mirabegron to Simulate Drug–Drug Interactions

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Abstract

Background and Objectives

Index substrates and inhibitors to investigate the role of the polymorphic enzyme, cytochrome P450 (CYP) 2D6, in the metabolism of new compounds have been proposed by regulatory agencies. This work describes the development and verification of physiologically-based pharmacokinetic (PBPK) models for the CYP2D6-sensitive substrate, nebivolol and the index CYP2D6 inhibitors, mirabegron and cinacalcet.

Methods

PBPK models for nebivolol, mirabegron and cinacalcet were developed using in vitro and clinical data. The performance of the PBPK models was verified by comparing the simulated results against reported human systemic exposure and clinical drug–drug interactions (DDIs) studies.

Results

The exposure of nebivolol, cinacalcet and mirabegron predicted by the PBPK models was verified against pharmacokinetic data from 13, 3 and 9 clinical studies, respectively. For nebivolol, the predicted mean maximum plasma concentration (Cmax) and area under the plasma concentration-time (AUC) values in CYP2D6 extensive metaboliser subjects were within 0.9- to 1.49-fold of the observed values. In poor metaboliser CYP2D6 subjects, the predicted Cmax and AUC values were within 0.41- to 0.81-fold of observed values. For cinacalcet, the predicted Cmax and AUC values were within 0.97- to 1.32-fold of the observed data. For mirabegron, the predicted AUC values across all the studies investigated were within 0.71- to 1.88-fold of observed values. The PBPK model-predicted DDIs were in good agreement (within 2-fold) with observed DDIs in all verification studies (n = 8) assessed. The overall precision was 1.26 and 1.21 for Cmax and the AUC ratio, respectively.

Conclusions

The developed PBPK models can be used to assess the DDI potential liability of new chemical entities that are substrates or inhibitors of CYP2D6.

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Authors and Affiliations

  1. Simcyp Division, Certara UK Limited, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK

    Peter Kilford, Nika Khoshaein, Roz Southall & Iain Gardner

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  1. Peter Kilford
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  2. Nika Khoshaein
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  3. Roz Southall
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Corresponding author

Correspondence to Roz Southall.

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Funding

The activities of Certara UK Limited, Simcyp Division is supported by the Simcyp Consortium of pharmaceutical companies. No other source of funding was used for the work.

Conflict of interest

Peter Kilford—at the time of the work was employed by Certara UK Limited and may hold shares in the company. Nika Khoshaein—at the time of the work was employed by Certara UK Limited and may hold shares in the company. Roz Southall—is employed by Certara UK Limited and may hold shares in the company. Iain Gardner—is employed by Certara UK Limited and may hold shares in the company.

Ethical approval

This was a simulation study and did not involve any clinical studies and therefore ethics approval was not needed.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

The workspaces used to run the simulation are available from the corresponding author on reasonable request.

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Author contributions

PK, NK, RS, IG wrote the manuscript; PK, NK designed the research; PK, NK, RS, IG performed the research; PK, NK analysed the data

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Kilford, P., Khoshaein, N., Southall, R. et al. Physiologically-Based Pharmacokinetic Models of CYP2D6 Substrate and Inhibitors Nebivolol, Cinacalcet and Mirabegron to Simulate Drug–Drug Interactions. Eur J Drug Metab Pharmacokinet 47, 699–710 (2022). https://doi.org/10.1007/s13318-022-00775-8

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