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

Introduction: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections. Areas covered: 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. Expert commentary: 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 > 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).

引言：本研究针对长效注射用帕利哌酮制剂（含每月一次注射制剂PP1M与每三月一次注射制剂PP3M）的治疗药物监测（Therapeutic Drug Monitoring, TDM）相关研究开展了汇总分析。
研究覆盖范围：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。以帕利哌酮浓度与给药剂量比值（C/D）作为清除率的评估指标，对3项稳态PP1M研究中的69例患者数据进行加权平均后，得到的C/D加权均值为7.7 ng·ml⁻¹/(mg·d⁻¹)，约为口服帕利哌酮的2倍。该C/D比值呈现以下特征：1）在12例老年患者中升高1.26倍；2）在肥胖患者中降低；3）在3例合并使用卡马西平的患者中降低50%。目前尚无具备临床意义的PP3M药代动力学研究数据发表。
专家评述：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治疗药物监测研究。早期治疗药物监测或可辅助PP1M的给药方案制定，但患者通常需至第9次注射（即给药8个月后）方可达到稳态血药浓度；PP3M制剂则可能需要超过1年的时间方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，而非直接由口服帕利哌酮转换；2）需熟练掌握帕利哌酮治疗药物监测技术，以用于治疗转换过程中的给药调整。对于存在清除率异常（如肥胖、老年年龄或合并使用强效肝药酶诱导剂）的患者，强烈推荐开展治疗药物监测。