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

<b>Introduction</b>: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations. <b>Areas covered</b>: Limited data is available on two formulations (RBP-7000 and <i>in Situ</i> 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 &gt;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. <b>Expert commentary</b>: 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.

<b>引言</b>：本系统综述针对治疗药物监测（therapeutic drug monitoring，TDM）展开，共纳入三款长效注射剂（long-acting injectable，LAI）利培酮制剂。<b>综述范围</b>：其中两款制剂（RBP-7000及原位微粒制剂（in Situ Microparticle））的相关数据较为有限，但针对微球制剂已检索到20篇治疗药物监测相关文献。利培酮的治疗药物监测涵盖利培酮及其活性代谢产物9-羟利培酮（9-hydroxyrisperidone）的血清浓度，用于计算两项指标：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（Cytochrome P450 2D6，CYP2D6）的代谢活性，比值＞1提示为CYP2D6弱代谢者）；2）利培酮总浓度-给药剂量（C/D）比值（用于反映利培酮的清除率，口服利培酮的正常参考值约为7 ng/ml/mg/天）。对6项利培酮长效注射剂研究中329名无主要混杂因素的患者进行合并分析后，其加权平均R/9-OH-R比值为0.48（约为口服利培酮治疗药物监测比值的2倍）。6项利培酮长效注射剂研究中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。<b>专家评述</b>：采用利培酮长效注射剂微球制剂开展治疗药物监测的临床医师需注意以下要点：1）首剂注射后需至少6周方可达到稳态血药浓度；2）需关注：a）合并使用的酶诱导剂/抑制剂类药物，b）重度炎症或感染情况，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的计算。