Model-Informed Clinical Development of 6-Monthly Injection of Paliperidone Palmitate in Patients with Schizophrenia: Dosing Strategies Guided by Population Pharmacokinetic Modeling and Simulation (Part II).

Autor: T'jollyn H; Janssen Research & Development, LLC, Turnhoutseweg 30, 2340, Beerse, Belgium. htjollyn@its.jnj.com., Venkatasubramanian R; Janssen Research & Development, LLC, Titusville, NJ, USA., Neyens M; Janssen Research & Development, LLC, Turnhoutseweg 30, 2340, Beerse, Belgium., Gopal S; Janssen Research & Development, LLC, Titusville, NJ, USA.; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Russu A; Janssen Research & Development, LLC, Turnhoutseweg 30, 2340, Beerse, Belgium., Nandy P; Janssen Research & Development, LLC, Raritan, NJ, USA.; CSL Behring, King of Prussia, PA, USA., Perez-Ruixo JJ; Janssen Research & Development, LLC, Turnhoutseweg 30, 2340, Beerse, Belgium., Ackaert O; Janssen Research & Development, LLC, 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. 491-506. Date of Electronic Publication: 2024 May 20.
DOI: 10.1007/s13318-024-00899-z
Abstrakt: Background and Objective: Paliperidone palmitate 6-month (PP6M) intramuscular (IM) injection is the longest-acting treatment available for patients with schizophrenia. A population pharmacokinetic (popPK) modeling and simulation approach was deployed to inform dosing strategies for PP6M.
Methods: The extensive analysis database included 15,932 paliperidone samples from 700 patients receiving gluteal paliperidone palmitate 3-month (PP3M) or PP6M injections in the double-blind phase of a phase-3 noninferiority study (NCT03345342). Exposure parameters for paliperidone appeared to increase dose-proportionally within each dosing schedule (PP3M/PP6M). The range of paliperidone exposures after IM administration of PP6M overlaps with that of corresponding doses of oral paliperidone extended release, PP 1-month (PP1M), and PP3M. Model-based simulations were performed to investigate paliperidone exposures in different PP6M dosing scenarios and relevant subpopulations.
Results: A dosing window of ≤ 2 weeks earlier and ≤ 3 weeks later than the target 6-month interval for maintenance treatment with PP6M dosing maintains paliperidone exposures at levels that are not expected to substantially impact its safety and efficacy. For missed-dose scenarios, tailored re-initiation regimens are proposed that should be applied before resuming PP6M maintenance dosing. Regarding subpopulations, PP6M 700 mg eq. is the highest dose recommended in mild renal-impairment patients; the paliperidone pharmacokinetics after PP6M administration is not affected by sex, body mass index, or age in a clinically meaningful way.
Conclusion: Paliperidone concentration-time profiles after PP6M and PP3M dosing were adequately described by the popPK model. Model-based simulation results provide guidance for clinicians on initiating PP6M therapy, transitioning between paliperidone formulations, the dosing windows to use for maintenance dosing, and managing missed PP6M doses.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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