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Model-Informed Clinical Development of Once-Every-6-Month Injection of Paliperidone Palmitate in Patients with Schizophrenia: A Pharmacometric Bridging Approach (Part I)

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

A model-informed drug development (MIDD) approach was implemented for paliperidone palmitate (PP) 6-month (PP6M) clinical development, using pharmacokinetics and pharmacokinetic/pharmacodynamic model-based simulations.

Methods

PP6M pharmacokinetics were simulated by extending the PP 3-month (PP3M) pharmacokinetic model to account for increased injection volume, and hence dose. Contribution of the MIDD approach to the design of the pivotal PP6M phase-3 study (PP6M/PP3M noninferiority study, NCT03345342) investigating schizophrenia relapse rates was twofold: (1) PP6M dose selection, and (2) hypothesis generation that lower trough concentrations (Ctrough) associated with PP6M, relative to PP3M, were not associated with lower efficacy, which was to be evaluated in the phase-3 study. Moreover, accompanied by an intense sampling scheme to adequately characterize paliperidone pharmacokinetics and to elucidate the potential relationship between concentration and safety/efficacy, the bridging strategy eliminated the need for additional phase-1/phase-2 clinical studies.

Results

Using a MIDD bridging strategy, PP6M doses were selected that, compared with PP3M, were expected to have a similar range of exposures and a noninferior relapse rate and safety profile. Clinical data from PP6M/PP3M noninferiority study confirmed that PP6M, compared with PP3M, had a similar range of exposures (T’jollyn et al. in Eur J Drug Metab Pharmacokinet 2024), as well as a noninferior relapse rate and safety profile (this manuscript).

Conclusions

Consistency of the MIDD approach with observed clinical outcomes confirmed the hypothesis that lower Ctrough did not lead to increased relapse rates at the doses administered. Although higher paliperidone peak concentrations are achieved with corresponding doses of PP6M relative to PP3M in the phase-3 clinical study, types and incidences of treatment-related adverse events were comparable between PP6M and PP3M groups and no new safety concerns emerged for PP6M (Najarian et al. in Int J Neuropsychopharmacol 25(3):238–251, 2022).

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Acknowledgements

Writing assistance was provided Uma Kundu, MPharm, CMPPTM (SIRO Clinpharm Pvt. Ltd.) and funded by Janssen Global Services, LLC and additional editorial support for this manuscript was provided by Ellen Baum, PhD (Janssen Global Services, LLC).

Author information

Author notes

  1. Srihari Gopal

    Present address: Regeneron Pharmaceuticals, Tarrytown, NY, USA

  2. Partha Nandy

    Present address: CSL Behring, King of Prussia, PA, USA

Authors and Affiliations

  1. Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Huybrecht T’jollyn, Alberto Russu, Martine Neyens, Ruben Faelens, Oliver Ackaert & Juan Jose Perez-Ruixo

  2. Janssen Research and Development, LLC, Titusville, NJ, USA

    Raja Venkatasubramanian, Srihari Gopal, Partha Nandy & Mahesh N. Samtani

Authors
  1. Huybrecht T’jollyn
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Corresponding author

Correspondence to Huybrecht T’jollyn.

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Author Contributions

SG, AR, PN, and JJPR conceptualized and designed the study; SG RV performed data collection; HT, AR, RV, OA, PN, and JJPR performed data analysis and interpretation; HT and AR performed manuscript writing. All authors reviewed and provided final approval for the manuscript and are accountable for all aspects of the work.

Funding

Janssen Research & Development, LLC, USA.

Conflict of Interest

Srihari Gopal was employed by Janssen Research & Development, LLC, USA when the study was conducted and is currently employed by Regeneron Pharmaceuticals, USA. Partha Nandy was employed by Janssen Research & Development, LLC, USA when the study was conducted and is currently employed by CSL Behring, USA. All other authors are employees of Janssen Research & Development, LLC (a Johnson & Johnson company) and hold stock in Johnson & Johnson.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and in adherence with the Good Clinical Practice guidelines and was approved by the institutional review board (as listed in the original research paper by Najarian et al.: A randomized, double-blind, multicenter, noninferiority study comparing paliperidone palmitate 6-month versus the 3-month long-acting injectable in patients with schizophrenia).

Informed consent

Informed consent was obtained from all patients before enrollment in the original study.

Consent for publication

Not applicable.

Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access [YODA] Project site at http://yoda.yale.edu.

Code Availability

The model equations are included in the Supplementary Material.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 336 KB)

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T’jollyn, H., Russu, A., Venkatasubramanian, R. et al. Model-Informed Clinical Development of Once-Every-6-Month Injection of Paliperidone Palmitate in Patients with Schizophrenia: A Pharmacometric Bridging Approach (Part I). Eur J Drug Metab Pharmacokinet (2024). https://doi.org/10.1007/s13318-024-00900-9

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