Abstract：
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
目的：帕利哌酮棕榈酸酯6个月（PP6M）肌内（IM）注射是精神分裂症患者可获得的最长有效治疗方法。采用群体药代动力学（popPK）建模和模拟方法来告知PP6M的给药策略。
方法：广泛的分析数据库包括来自700名患者的15,932份帕潘立酮样本，这些患者在3期非劣效性研究（NCT03345342）的双盲阶段接受了3个月的臀部帕潘立酮棕榈酸酯（PP3M）或PP6M注射。帕潘立酮的暴露参数在每个给药方案(PP3M/PP6M)内似乎成比例地增加剂量。IM给药PP6M后的帕潘立酮暴露范围与相应剂量的口服帕潘立酮缓释剂重叠，PP1个月(PP1M),和PP3M。进行基于模型的模拟以研究不同PP6M给药方案和相关亚群中的帕潘立酮暴露。
结果：与PP6M给药维持治疗的目标6个月间隔相比，提前≤2周和晚≤3周的给药窗口维持帕潘立酮暴露在预期不会显著影响其安全性和有效性的水平。对于错过剂量的情况，建议在恢复PP6M维持给药之前应用量身定制的重新开始方案。关于亚群，PP6M700mgeq.是轻度肾功能损害患者推荐的最高剂量;PP6M给药后的帕潘立酮药代动力学不受性别影响，身体质量指数,或年龄在临床上有意义的方式。
结论：popPK模型充分描述了PP6M和PP3M给药后的帕潘立酮浓度-时间曲线。基于模型的仿真结果为临床医生开始PP6M治疗提供指导，帕潘立酮制剂之间的过渡，用于维护加药的加药窗口，和管理错过的PP6M剂量。
方法：广泛的分析数据库包括来自700名患者的15,932份帕潘立酮样本，这些患者在3期非劣效性研究（NCT03345342）的双盲阶段接受了3个月的臀部帕潘立酮棕榈酸酯（PP3M）或PP6M注射。帕潘立酮的暴露参数在每个给药方案(PP3M/PP6M)内似乎成比例地增加剂量。IM给药PP6M后的帕潘立酮暴露范围与相应剂量的口服帕潘立酮缓释剂重叠，PP1个月(PP1M),和PP3M。进行基于模型的模拟以研究不同PP6M给药方案和相关亚群中的帕潘立酮暴露。
结果：与PP6M给药维持治疗的目标6个月间隔相比，提前≤2周和晚≤3周的给药窗口维持帕潘立酮暴露在预期不会显著影响其安全性和有效性的水平。对于错过剂量的情况，建议在恢复PP6M维持给药之前应用量身定制的重新开始方案。关于亚群，PP6M700mgeq.是轻度肾功能损害患者推荐的最高剂量;PP6M给药后的帕潘立酮药代动力学不受性别影响，身体质量指数,或年龄在临床上有意义的方式。
结论：popPK模型充分描述了PP6M和PP3M给药后的帕潘立酮浓度-时间曲线。基于模型的仿真结果为临床医生开始PP6M治疗提供指导，帕潘立酮制剂之间的过渡，用于维护加药的加药窗口，和管理错过的PP6M剂量。
