Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia A Novel Once-Monthly, Long-Acting Formulation of an Atypical Antipsychotic
Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia A Novel Once-Monthly, Long-Acting Formulation of an Atypical Antipsychotic
复制标题
DOI：
10.2165/11316870-000000000-00000
复制
发表时间：
2009-01-01
影响因子：
4.5
通讯作者：
Stuyckens, Kim
中科院分区：
文献类型：
--
作者：
Samtani, Mahesh N.;Vermeulen, An;Stuyckens, Kim
目的：研究帕利哌酮长效棕榈酸酯在不同剂量和两个不同注射部位(三角肌和臀肌)肌肉注射后的群体药代动力学特征。方法：回顾分析6个I期试验和5个II、III期试验的1795例受试者的总体药代动力学。共有18530个具有有效浓度时间点的药代动力学样本可用于该分析。使用NONMEM(R)软件对合并数据进行非线性混合效应建模。整个数据集被分为索引数据集(模型开发)和验证数据集。结果：帕利培酮肌肉注射棕榈酸酯后的血药浓度-时间数据符合一阶消去一室模型。该模型的吸收成分允许一小部分剂量(f(2))通过零级过程相对快速地进入中央隔室。在一段滞后时间后，剩余的部分通过一级过程进入系统循环。清除量(CL)、中心分布体积(V-d)和吸收速率常数(k(A))的个体间变异系数(CV)分别为40%、69%和59%。通过Logit变换拟合帕利哌酮双输入法吸收的f(2)上的IIV，其标准偏差(SD)为0.064。CL、V-d和f(2)的变异系数(IOV)分别为26%、14%和0.07%SD。用对数变换数据的加性误差模型描述残差，其标准偏差为0.22。最终的协变量模型显示以下变量对k(A)有显著影响：性别、年龄、注射量(IVOL)和注射部位(INJS)。同样，以下变量对172有显著影响：性别、体重指数(BMI)、针头长度(NDLL)、INJS和IVOL。此外，CL与内生肌酐清除量(CLcr)有关，而VD与BMI和性别有关。结论：帕利培克隆肌肉注射棕榈酸酯后，符合双吸收药动学模型。这些结果表明，帕利哌酮棕榈酸酯的药代动力学主要受BMI、CLcr、INJS、IVOL和NDLL的影响。
Objectives: To characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle).Methods: The retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III trials. A total of 18 530 pharmacokinetic samples with valid concentration timepoints were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM (R) software. The full dataset was divided into an index dataset (model development) and a validation dataset. After validation both the index and validation datasets were combined and the final model was re-run on the full dataset.Results: The concentration-time data for paliperidone following intramuscular administration of its palmitate ester were best fitted to a one-compartment model with first-order elimination. The absorption component of the model allowed a fraction of the dose (f(2)) to enter relatively quickly into the central compartment via a zero-order process. After a lag time, the remaining fraction then entered the system circulation via a first-order process. Interindividual variability (IIV) in clearance (CL), central volume of distribution (V-d) and the absorption rate constant (k(a)) were estimated at a 40%, 69% and 59% coefficient of variation (CV), respectively. The IIV on f(2) for paliperidone absorption via the dual-input process was fitted through logit transformation, and its standard deviation (SD) was 0.064. Similarly, the interoccasion variability (IOV) on CL, V-d and f(2) was 26% CV, 14% CV and 0.07 SD, respectively. An additive-error model with log-transformed data was used to describe the residual variability (RV), and its SD was 0.22. The final covariate model indicated that the following variables had a significant influence on k(a): sex, age, injection volume (IVOL) and injection site (INJS). Similarly, the following variables had a significant influence on 172: sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CLCR), whereas Vd was related to BMI and sex.Conclusions: A dual-absorption pharmacokinetic model best described the complex pharmacokinetics of palipericlone after intramuscular administration of its palmitate ester. These results suggest that the pharmacokinetics of paliperidone palmitate are mostly influenced by BMI, CLCR, INJS, IVOL and NDLL.