Predicting Plasma Concentration of Risperidone Associated With Dosage Change: A Population Pharmacokinetic Study
Predicting Plasma Concentration of Risperidone Associated With Dosage Change: A Population Pharmacokinetic Study
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DOI：
10.1097/ftd.0b013e3182489a6f
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发表时间：
2012-04
影响因子：
2.5
通讯作者：
H. Uchida;D. Mamo;B. Pollock;Takefumi Suzuki;K. Tsunoda;Koichiro Watanabe;M. Mimura;R. Bies
中科院分区：
文献类型：
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作者：
H. Uchida;D. Mamo;B. Pollock;Takefumi Suzuki;K. Tsunoda;Koichiro Watanabe;M. Mimura;R. Bies
背景由于外周药代动力学参数的个体间高度变异性，抗精神病药物的剂量依赖于临床试验和错误。这种盲目的向上或向下临床剂量滴定过程在精神分裂症的治疗中存在复发和不良反应的风险。因此，利用群体药代动力学方法，作者试图在剂量改变之前预测利培酮(RIS)和9-羟基利培酮(9-OH-RIS)的血药浓度。方法对50例服用利培酮的精神分裂症或分裂情感性精神障碍患者(平均年龄56±15岁，男性39例)在两个不同的时间点采集两份血浆标本，测定RIS和9-OH-RIS浓度。在口服利培酮剂量调整后，收集了第三个样本。第三个样本的血药浓度与剂量调整前的两个基线血药浓度以及临床和人口学信息采用盲法分别预测，采用NONMEM混合效应模型，该模型来自于干预效果研究中的临床抗精神病药物试验数据。结果RIS的平均预测误差(95%可信区间)为0(−1.3~1.4)，9-OH RIS的预测误差为1.0(−1.1~3.0)。RIS和9-OH-RIS的观测值和预测值高度相关(r=0.96P<；0.0001和r=0.92P<；0.0001)。结论在利培酮剂量调整前，可以预测抗精神病药物的血药浓度。根据已知的血浆药物浓度、多巴胺D2受体占有率和临床疗效之间的关系，我们的结果证实了通过测量抗精神病药物血浆浓度的个体化给药具有床边临床应用的潜力。
Background Due to high interindividual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics relies on clinical trial and error. This blind process of upward or downward clinical dose titration carries a risk of relapse and adverse effects in the treatment of schizophrenia. Using population pharmacokinetic methods, the authors therefore sought to predict plasma concentrations of risperidone (RIS) plus 9-hydroxyrisperidone (9-OH-RIS) before a dosage change. Methods Two plasma samples were collected at 2 separate given time points for the measurement of RIS and 9-OH-RIS concentrations from 50 patients with schizophrenia or schizoaffective disorder maintained on risperidone (mean ± SD age = 56 ± 15 years; 39 men). After an oral risperidone dose adjustment, a third sample was collected. The plasma concentration of the third sample was individually predicted in a blinded fashion with the 2 baseline plasma concentrations before dose adjustment and clinical and demographic information, using the mixed-effects model with NONMEM that was derived from the data of the Clinical Antipsychotic Trials in Intervention Effectiveness study. Results The mean (95% confidence interval) prediction errors (in ng/mL) were as low as 0.0 (−1.3 to 1.4) for RIS and 1.0 (−1.1 to 3.0) for 9-OH-RIS. The observed and predicted concentrations of RIS and 9-OH-RIS were highly correlated (r = 0.96, P < 0.0001 and r = 0.92, P < 0.0001, respectively). Conclusions Antipsychotic plasma concentrations can be predicted before risperidone dose adjustment. In light of the known relationship between plasma drug concentration, dopamine D2 receptor occupancy, and clinical effects, our results confirm that individualized dosing with the measurement of antipsychotic plasma concentrations has the potential for bedside clinical application.