Pelligand L, Soubret A, King J N, Elliott J, Mochel J P
Royal Veterinary College, Hatfield, United Kingdom.
Department of Pharmacometrics, Novartis Pharmaceuticals, Basel, Switzerland.
CPT Pharmacometrics Syst Pharmacol. 2016 Nov;5(11):625-635. doi: 10.1002/psp4.12141. Epub 2016 Oct 22.
The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed-effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first-order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (K = 0.68 h ) was lower than beta (median, 1.08 h ), unveiling flip-flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population.
本研究的目的是使用非线性混合效应（NLME）方法对罗贝考昔在猫体内的药代动力学（PK）进行建模，利用从接受罗贝考昔皮下和/或静脉注射的猫收集的所有可用信息：47只密集采样的实验猫和36只术前稀疏采样的临床猫。使用Monolix 4.3.2对来自两种给药途径的数据进行顺序建模。通过使用来自随机效应后验分布的多个样本，评估参数相关性和可用协变量（年龄、性别、体重和麻醉）对群体参数估计的影响。具有同时零阶和一阶吸收的双室处置模型最能描述罗贝考昔在血液中的PK。清除率为0.502 L/kg/h，生物利用度较高（78%）。吸收常数点估计值（K = 0.68 h）低于β（中位数，1.08 h），揭示了反转动力学。不主张根据可用的协变量信息进行剂量调整。这项建模工作是NLME在大型猫科动物群体中的首次应用。
