Aman Michael G, Vinks Alexander A, Remmerie Bart, Mannaert Erik, Ramadan Yaser, Masty Jessica, Lindsay Ronald L, Malone Krista
The Nisonger Center, The Ohio State University, Columbus, Ohio 43210, USA.
Clin Ther. 2007 Jul;29(7):1476-86. doi: 10.1016/j.clinthera.2007.07.026.
Risperidone is a second-generation antipsychotic agent widely used in the treatment of schizophrenia and other psychotic disorders in adults. Risperidone is probably the most frequently used atypical antipsychotic in the pediatric population.
The goals of this study were to estimate the pharmacokinetic parameters of risperidone and its enantiomers in a pediatric population and explore relationships between saliva and plasma concentrations.
Eligible patients, between 4 and 15 years of age, included those taking a stable dose of oral risperidone ranging from 0.01 to 0.07 mg/kg BID for > or =4 weeks to treat psychiatric or neurodevelopmental conditions. A trough blood level and predose saliva sample were collected at study initiation; the regular risperidone dose was administered; and paired samples of blood and saliva were collected at 1, 2, 4, and 7 hours postdose. Plasma/saliva concentrations of risperidone and enantiomers of its principal active metabolite, 9-hydroxyrisperidone (9-OH-risperidone), were measured using a chiral liquid chromatography-tandem mass spectrometry assay. Standard pharmacokinetic parameters were calculated. Cytochrome P450 2D6 genotypes of *3,*4,*5 deletion and duplication were determined.
The study included 19 patients (age range, 4 years 2 months to 15 years 11 months). Mean (SD) values for C(max), t(1/2), and AUC 0 to 12 hours for risperidone in plasma were 15.9 (22.2) ng/mL, 3.0 (2.3) h, and 92.1 (200.6) ng x h/mL, respectively. Corresponding values in saliva were 12.0 (21.0) ng/mL, 3.4 (3.2) h, and 27.8 (38.7) ng x h/mL, respectively. Mean (SD) plasma enantiomer values for C(max) and AUC calculated up to the last observation were: (+)-9-OH-risperidone, 13.6 (10.0) ng/mL and 73.6 (52.3) ng x h/mL; (-)-9-OH-risperidone, 4.9 (3.1) ng/mL and 29.3 (19.1) ng x h/mL. Corresponding enantiomer values in saliva were: (+)-9-OH-risperidone, 5.2 (8.8) ng/mL and 15.6 (8.9) ng x h/mL; (-)-9-OH-risperidone, 5.0 (7.9) ng/mL and 15.6 (9.1) ng x h/mL, respectively. Large interindividual variability in risperidone and enantiomer concentrations was noted. A highly significant relationship between predose plasma and predose saliva risperidone concentrations was observed. The logarithmic regression model indicated that the log risperidone saliva concentration = -0.100 + 0.594 x log plasma concentration (R(2) = 0.93 [Spearman]).
In this preliminary pharmacokinetic study of parameters for risperidone and the enantiomers of 9-OH-risperidone in a pediatric population, mean C(max) and t(1/2) of risperidone were generally similar to those previously described in adults. The highly significant relationship between predose plasma and predose saliva risperidone concentrations suggests that saliva measurements may be a viable alternative to plasma sampling in children.
利培酮是一种第二代抗精神病药物，广泛用于治疗成人精神分裂症和其他精神障碍。利培酮可能是儿科人群中最常用的非典型抗精神病药物。
本研究的目的是估计利培酮及其对映体在儿科人群中的药代动力学参数，并探讨唾液浓度与血浆浓度之间的关系。
符合条件的患者年龄在4至15岁之间，包括那些服用稳定剂量的口服利培酮（0.01至0.07mg/kg，每日两次）超过或等于4周以治疗精神或神经发育疾病的患者。在研究开始时采集谷血药浓度和给药前唾液样本；给予常规利培酮剂量；并在给药后1、2、4和7小时采集配对的血液和唾液样本。使用手性液相色谱 - 串联质谱分析法测量血浆/唾液中利培酮及其主要活性代谢物9 - 羟基利培酮（9-OH-利培酮）的对映体浓度。计算标准药代动力学参数。测定细胞色素P450 2D6基因*3、*4、*5的缺失和重复基因型。
该研究纳入了19名患者（年龄范围为4岁2个月至15岁11个月）。血浆中利培酮的C(max)、t(1/2)和0至12小时AUC的平均值（标准差）分别为15.9（22.2）ng/mL、3.0（2.3）小时和92.1（200.6）ng·h/mL。唾液中的相应值分别为12.0（21.0）ng/mL、3.4（3.2）小时和27.8（38.7）ng·h/mL。计算至最后一次观察的血浆对映体C(max)和AUC的平均值（标准差）为：(+)-9-OH-利培酮，13.6（10.0）ng/mL和73.6（52.3）ng·h/mL；(-)-9-OH-利培酮，4.9（3.1）ng/mL和29.3（19.1）ng·h/mL。唾液中的相应对映体值为：(+)-9-OH-利培酮，5.2（8.8）ng/mL和15.6（8.9）ng·h/mL；(-)-9-OH-利培酮，5.0（7.9）ng/mL和15.6（9.1）ng·h/mL。注意到利培酮及其对映体浓度存在较大的个体间差异。观察到给药前血浆和给药前唾液中利培酮浓度之间存在高度显著的关系。对数回归模型表明，利培酮唾液浓度的对数=-0.100 + 0.594×血浆浓度的对数（R² = 0.93 [Spearman]）。
在这项关于利培酮和9-OH-利培酮对映体在儿科人群中药代动力学参数的初步研究中，利培酮的平均C(max)和t(1/2)通常与先前在成人中描述的相似。给药前血浆和给药前唾液中利培酮浓度之间的高度显著关系表明，唾液测量可能是儿童血浆采样的一种可行替代方法。
