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

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations. Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value around 7 in oral risperidone). The weighted mean R/9-OH-R ratio was 0.48 (approximately twice that of oral risperidone TDM) in a combined analysis from 329 patients in 6 risperidone LAI studies without major confounders. The total C/D ratios from 297 patients in 6 risperidone LAI studies ranged from 7.4 to 9.7 ng/ml/mg/day with a weighted mean of 8.8 ng/ml/mg/day. Expert commentary: Clinicians using TDM for risperidone LAI microsphere formulation need to: 1) consider steady state to be reached ≥ 6 weeks after the first injection, 2) pay attention to a) co-medications with inducers/inhibitors, b) severe inflammations/infections, and c) hepatic/renal impairment, and 3) use Castberg’s recommendation to calculate risperidone dosing.

引言：本系统综述围绕治疗药物监测（Therapeutic Drug Monitoring，TDM）展开，共梳理出三种利培酮长效注射剂（Long-acting Injectable，LAI）制剂。
研究覆盖领域：目前针对其中两种制剂（RBP-7000与原位微球制剂（in Situ Microparticle））的相关数据较为匮乏，但已检索到20篇针对微球制剂的利培酮TDM相关研究文献。利培酮TDM检测指标包括利培酮及其活性代谢产物9-羟利培酮的血清浓度，用于计算两项核心参数：1）利培酮/9-羟利培酮（R/9-OH-R）比值（用于反映细胞色素P450 2D6（CYP2D6）的代谢表型，比值＞1提示为CYP2D6慢代谢者）；2）利培酮总浓度与给药剂量之比（C/D比值，用于评估利培酮的机体清除率，口服利培酮的正常C/D比值约为7）。对6项利培酮LAI研究中329名无主要混杂因素患者的合并分析显示，加权平均R/9-OH-R比值为0.48，约为口服利培酮TDM对应比值的两倍。6项利培酮LAI研究中297名患者的总C/D比值范围为7.4~9.7 ng/ml/mg/天，加权平均值为8.8 ng/ml/mg/天。
专家评论：临床医师若采用利培酮微球制剂的TDM指导临床用药，需遵循以下要点：1）确认首次注射后至少6周方可达到稳态血药浓度；2）需重点关注以下情况：a）合并使用CYP450酶诱导剂或抑制剂的药物，b）严重炎症或感染，c）肝肾功能损害；3）参考Castberg的推荐方案进行利培酮给药剂量计算。