Janssen Research & Development, LLC, Turnhoutseweg 30, 2340, Beerse, Belgium.
Janssen Research & Development, LLC, Titusville, NJ, USA.
Eur J Drug Metab Pharmacokinet. 2024 Jul;49(4):491-506. doi: 10.1007/s13318-024-00899-z. Epub 2024 May 20.
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.
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.
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.
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.
棕榈酸帕利哌酮 6 个月（PP6M）肌内（IM）注射是目前治疗精神分裂症患者的最长效治疗方法。采用群体药代动力学（popPK）建模和模拟方法为 PP6M 的给药策略提供信息。
广泛的分析数据库包括 700 名接受臀部棕榈酸帕利哌酮 3 个月（PP3M）或 PP6M 注射的患者的 15932 个帕利哌酮样本，这些患者在一项 3 期非劣效性研究（NCT03345342）的双盲期接受了治疗。在每个给药方案（PP3M/PP6M）内，帕利哌酮的暴露参数似乎呈剂量比例增加。IM 给予 PP6M 后的帕利哌酮暴露范围与相应剂量的口服帕利哌酮延长释放制剂 PP1M 和 PP3M 重叠。进行基于模型的模拟以研究不同的 PP6M 给药方案和相关亚人群中的帕利哌酮暴露情况。
PP6M 维持治疗的目标 6 个月间隔提前≤2 周和延迟≤3 周的给药窗口可维持帕利哌酮的暴露水平，预计不会对其安全性和疗效产生重大影响。对于漏服剂量情况，建议制定定制的重新开始方案，应在重新开始 PP6M 维持剂量之前应用。关于亚人群，PP6M700mg eq. 是轻度肾功能损害患者推荐的最高剂量；PP6M 给药后帕利哌酮的药代动力学不受性别、体重指数或年龄的临床意义上的影响。
PP6M 和 PP3M 给药后的帕利哌酮浓度-时间曲线由 popPK 模型充分描述。基于模型的模拟结果为临床医生提供了启动 PP6M 治疗、在帕利哌酮制剂之间转换、维持剂量使用的给药窗口以及管理漏用 PP6M 剂量的指导。
