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Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model

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Abstract

Background and Objective

A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug–drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO®). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs.

Methods

The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp® v14.1 by combining the oral and intravenous esketamine PBPK models, with the dose divided in the ratio 57.7/42.3. Verification of the model was based on comparing the pharmacokinetics and DDI simulations with observed data in healthy volunteers.

Results

The simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions.

Conclusion

This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO®.

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Acknowledgements

Priya Ganpathy, MPharm CMPP (SIRO Clinpharm Pvt. Ltd., India), provided writing assistance. Ellen Baum, PhD, and Harry Ma, PhD CMPP (both Janssen Global Services, LLC) provided additional editorial support. The authors thank the patients and investigators for their participation in the study.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Janssen Pharmaceutical Companies of Johnson & Johnson, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Marie-Emilie Willemin, Geert Mannens, Loeckie de Zwart & Jan Snoeys

  2. Janssen Research & Development, LLC, New Jersey, USA

    Peter Zannikos

Authors
  1. Marie-Emilie Willemin
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Corresponding author

Correspondence to Marie-Emilie Willemin.

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Funding

This study was funded by Janssen Research & Development, LLC.

Conflicts of Interest

Marie-Emilie Willemin, Peter Zannikos, Geert Mannens, Loeckie de Zwart, and Jan Snoeys are employees of Janssen Research & Development, LLC, and may hold company stocks or stock options.

Ethics approval

Institutional review boards or independent ethics committees approved the study protocols of all primary pharmacokinetic and DDI studies. The studies were conducted in accordance with the ethical principles of the Declaration of Helsinki, good clinical practice, and applicable regulatory requirements.

Consent to participate

All participants provided written consent to participate

Consent for Publication

All authors read and approved the manuscript for publication, agreed on the journal to which the article was submitted, and agreed to be accountable for all aspects of the work.

Availability of Data and Material

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. Requests for access to the study data can be submitted through Yale Open Data Access Project site at http://yoda.yale.edu.

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Not applicable.

Author contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

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Willemin, ME., Zannikos, P., Mannens, G. et al. Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model. Clin Pharmacokinet 61, 1115–1128 (2022). https://doi.org/10.1007/s40262-022-01123-4

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