Alvariza Silvana, Ibarra Manuel, Guevara Natalia, Maldonado Cecilia, Vázquez Marta, Feijoó Gimena, Suárez Gonzalo
Department of Clinical and Veterinary Hospital, Faculty of Veterinary, Pharmacology and Therapeutics Unit, Universidad de la República, Montevideo, Uruguay.
Pharmaceutical Sciences Department, Therapeutic Drug Monitoring Service, Faculty of Chemistry, University Hospital, Montevideo, Uruguay.
Front Vet Sci. 2025 Sep 3;12:1644003. doi: 10.3389/fvets.2025.1644003. eCollection 2025.
Phenobarbital (PB) remains the first-line treatment for canine epilepsy due to its efficacy, affordability, and favorable pharmacokinetics. However, its narrow therapeutic index and substantial interindividual variability necessitate therapeutic drug monitoring (TDM) and individualized dosing. This study aimed to develop and validate a population pharmacokinetic (popPK) model of PB in dogs to support model-informed precision dosing (MIPD) in clinical practice.
A total of 121 serum samples from 100 dogs receiving PB monotherapy at steady state were used to build the model. An external dataset comprising 53 samples from 50 dogs was used for validation. Modeling was performed using nonlinear mixed-effects (NLME) techniques in MonolixSuite 2023R1. Covariate analysis included age, sex, and body weight (WT). Model performance was assessed using goodness-of-fit plots, prediction-corrected visual predictive checks (pcVPC), and calculation of mean error (ME), mean relative error (MRE), and root mean square error (RMSE). Monte Carlo simulations were conducted to evaluate the probability of target attainment (PTA) under different dosing regimens.
A one-compartment model with autoinductive clearance (CL) best described PB pharmacokinetics. WT and age were significant covariates on apparent clearance (CL/F). The model accurately predicted PB concentrations in the external dataset (ME = -0.08 mg/L, MRE = 0.04%, RMSE = 2.04%). Simulations identified optimal dosing regimens stratified by age and WT, including recommendations for loading doses to accelerate attainment of therapeutic concentrations.
The validated popPK model enables individualized PB dosing in dogs, accounting for variability in WT and age. This approach supports the implementation of MIPD in veterinary practice and may improve therapeutic outcomes while minimizing toxicity.
由于苯巴比妥（PB）疗效确切、价格低廉且药代动力学良好，它仍是犬癫痫的一线治疗药物。然而，其治疗指数狭窄且个体间差异较大，因此需要进行治疗药物监测（TDM）和个体化给药。本研究旨在建立并验证犬PB的群体药代动力学（popPK）模型，以支持临床实践中的模型指导精准给药（MIPD）。
共使用了100只接受PB单药治疗且处于稳态的犬的121份血清样本建立模型。一个包含50只犬的53份样本的外部数据集用于验证。使用MonolixSuite 2023R1中的非线性混合效应（NLME）技术进行建模。协变量分析包括年龄、性别和体重（WT）。使用拟合优度图、预测校正视觉预测检查（pcVPC）以及计算平均误差（ME）、平均相对误差（MRE）和均方根误差（RMSE）来评估模型性能。进行蒙特卡洛模拟以评估不同给药方案下达到目标的概率（PTA）。
具有自动诱导清除率（CL）的一室模型最能描述PB的药代动力学。WT和年龄是表观清除率（CL/F）的显著协变量。该模型准确预测了外部数据集中的PB浓度（ME = -0.08 mg/L，MRE = 0.04%，RMSE = 2.04%）。模拟确定了按年龄和WT分层的最佳给药方案，包括关于负荷剂量的建议以加速达到治疗浓度。
经过验证的popPK模型能够实现犬PB的个体化给药，同时考虑到WT和年龄的变异性。这种方法支持在兽医实践中实施MIPD，并可能改善治疗效果，同时将毒性降至最低。
