A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone

<b>Introduction</b>: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections. <b>Areas covered</b>: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from three steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in three patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data have been published. <b>Expert commentary</b>: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the ninth injection (8 months). PP3M may take &gt; 1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers).

<b>引言</b>：本研究针对长效注射用帕利哌酮制剂——每月一次注射剂（PP1M）与每三月一次注射剂（PP3M）的治疗药物监测（therapeutic drug monitoring, TDM）相关研究开展了整合分析。<b>涵盖范围</b>：本研究共纳入14篇PP1M相关研究文献与1篇PP3M相关研究文献。以帕利哌酮浓度/剂量（C/D）比值作为清除率的衡量指标，对来自3项稳态PP1M研究的69例患者进行加权分析后，得到加权平均C/D比值为7.7 ng·ml⁻¹/(mg·d⁻¹)，该值为口服帕利哌酮的2倍。C/D比值的特征如下：1）12例老年患者的C/D比值高出1.26倍；2）肥胖患者的C/D比值更低；3）3例合用卡马西平的患者的C/D比值降低50%。目前尚未有具备临床意义的PP3M药代动力学研究数据发表。<b>专家评述</b>：当前亟需开展半衰期相关研究，以及更多采用稳态设计的PP1M TDM研究。早期TDM研究或有助于指导PP1M的给药方案，但患者通常需至第9次注射后（即治疗8个月后）才能达到稳态血药浓度。PP3M制剂可能需要超过1年的时间才能达到稳态血药浓度。对于考虑将患者转换为PP1M治疗的临床医师：1）应优先将口服利培酮转换为PP1M，而非直接从口服帕利哌酮转换；2）应熟练掌握帕利哌酮TDM技术，以用于治疗转换过程中。对于存在清除异常（如肥胖、老年年龄或合用强效肝药酶诱导剂）的患者，强烈建议开展TDM监测。