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

Autor: T'jollyn H; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium. htjollyn@its.jnj.com., Russu A; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium., Venkatasubramanian R; Janssen Research and Development, LLC, Titusville, NJ, USA., Gopal S; Janssen Research and Development, LLC, Titusville, NJ, USA.; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Nandy P; Janssen Research and Development, LLC, Titusville, NJ, USA.; CSL Behring, King of Prussia, PA, USA., Neyens M; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium., Faelens R; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium., Samtani MN; Janssen Research and Development, LLC, Titusville, NJ, USA., Ackaert O; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium., Perez-Ruixo JJ; Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
Jazyk: angličtina
Zdroj: European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2024 Jul; Vol. 49 (4), pp. 477-489. Date of Electronic Publication: 2024 May 15.
DOI: 10.1007/s13318-024-00900-9
Abstrakt: 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 (C trough ) 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 C trough 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).
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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