Samtani Mahesh N, Vermeulen An, Stuyckens Kim
Clinical Pharmacology, Advanced PK-PD Modeling & Simulation, Johnson & Johnson Pharmaceutical Research & Development, LLC, 920 Route 202, PRD 2723, Raritan, NJ 08869, USA.
Clin Pharmacokinet. 2009;48(9):585-600. doi: 10.2165/11316870-000000000-00000.
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).
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 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.
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 systemic 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 f(2): sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CL(CR)), whereas V(d) was related to BMI and sex.
A dual-absorption pharmacokinetic model best described the complex pharmacokinetics of paliperidone after intramuscular administration of its palmitate ester. These results suggest that the pharmacokinetics of paliperidone palmitate are mostly influenced by BMI, CL(CR), INJS, IVOL and NDLL.
在不同剂量以及两个不同注射部位（三角肌和臀大肌）肌肉注射长效棕榈酸帕利哌酮酯后，对帕利哌酮的群体药代动力学特征进行描述。
回顾性分析纳入了来自六项I期试验以及五项II期和III期试验的1795名受试者的汇总数据。本分析共有18530个具有有效浓度时间点的药代动力学样本。使用NONMEM软件对汇总数据进行非线性混合效应建模。完整数据集被分为一个索引数据集（模型开发）和一个验证数据集。验证后，将索引数据集和验证数据集合并，并在完整数据集上重新运行最终模型。
肌肉注射棕榈酸帕利哌酮酯后，帕利哌酮的浓度 - 时间数据最适合具有一级消除的单室模型。该模型的吸收成分允许一部分剂量（f(2)）通过零级过程相对快速地进入中央室。经过一段滞后时间后，其余部分随后通过一级过程进入体循环。清除率（CL）、中央分布容积（V(d)）和吸收速率常数（k(a)）的个体间变异性（IIV）分别以40%、69%和59%的变异系数（CV）进行估计。通过logit变换拟合了帕利哌酮经双输入过程吸收的f(2)上的IIV，其标准差（SD）为0.064。同样，CL、V(d)和f(2)的个体间变异性（IOV）分别为26%CV、14%CV和0.07SD。使用具有对数变换数据的加性误差模型来描述残差变异性（RV），其SD为0.22。最终的协变量模型表明，以下变量对k(a)有显著影响：性别、年龄、注射体积（IVOL）和注射部位（INJS）。同样，以下变量对f(2)有显著影响：性别、体重指数（BMI）、针长（NDLL）、INJS和IVOL。此外，CL与肌酐清除率（CL(CR)）相关，而V(d)与BMI和性别相关。
双吸收药代动力学模型最能描述肌肉注射棕榈酸帕利哌酮酯后帕利哌酮复杂的药代动力学特征。这些结果表明，棕榈酸帕利哌酮的药代动力学主要受BMI、CL(CR)、INJS、IVOL和NDLL的影响。
