Cross Charlotte, Martinez Marilyn N, Pade Devendra, Myers Michael J, Neuhoff Sibylle
Certara UK Ltd., Certara Predictive Technologies, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK.
Office of Generic Animal Drugs, Center for Veterinary Medicine, Food and Drug Administration, Rockville, Maryland, 20855, USA.
AAPS J. 2025 Jun 2;27(4):101. doi: 10.1208/s12248-025-01061-6.
A bottom-up physiologically based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of loperamide, a substrate for multidrug resistance 1 (Mdr1) encoded P-glycoprotein (P-gp), in wild-type dogs (WT) and dogs that are homozygous for a base-pair deletion in the Mdr1 gene encoding for P-gp (Mu, Δ-Mdr1). In vitro-to-in vivo extrapolation (IVIVE) techniques were employed where in vitro data describing loperamide absorption, distribution, metabolism, and elimination (ADME) were extrapolated to in vivo dose exposure predictions. Importantly, by applying system parameters extrapolated from other breeds and published information on Collie-specific physiology, for the first time, a breed-specific whole-body PBPK model for the Collie was developed. Using our loperamide IVIVE-PBPK model (Simcyp Animal Simulator), the observed plasma concentration-versus-time profiles after intravenous and oral loperamide administration were successfully captured. The overall model performance for the WT (n = 7) and Mu (n = 10) Collies was within 1.40 and 1.24, and 1.18 and 1.51 AAFE for the Area under the plasma concentration-time-profile curve (AUC) and maximal plasma concentration (C) predictions, respectively. Predicted C values were within ± 25% of observed values for 67% of all doses for the WT dogs. For the Mu dogs, the predicted AUC was within 50% for all doses. Our work provides the first example of a systematic approach for Collies and illustrates its use to describe the impact of a known genetic variation in the canine Mdr1 gene. Furthermore, we describe the general workflow for establishing, verifying, and applying an IVIVE-PBPK framework for predicting in vivo drug behavior within a specific canine breed.
建立了一个自下而上的基于生理的药代动力学（PBPK）模型，以预测洛哌丁胺（一种由多药耐药性1（Mdr1）编码的P-糖蛋白（P-gp）的底物）在野生型犬（WT）和Mdr1基因中编码P-gp的碱基对缺失纯合的犬（Mu，Δ-Mdr1）体内的药代动力学。采用体外到体内外推（IVIVE）技术，将描述洛哌丁胺吸收、分布、代谢和消除（ADME）的体外数据外推到体内剂量暴露预测。重要的是，通过应用从其他品种推断的系统参数以及关于柯利牧羊犬特定生理学的已发表信息，首次开发了柯利牧羊犬的品种特异性全身PBPK模型。使用我们的洛哌丁胺IVIVE-PBPK模型（Simcyp动物模拟器），成功捕获了静脉内和口服洛哌丁胺给药后观察到的血浆浓度-时间曲线。WT（n = 7）和Mu（n = 10）柯利牧羊犬的总体模型性能在血浆浓度-时间曲线下面积（AUC）预测的1.40和1.24以及最大血浆浓度（C）预测的1.18和1.51平均预测误差因子（AAFE）范围内。对于WT犬，67%的所有剂量的预测C值在观察值的±25%范围内。对于Mu犬，所有剂量的预测AUC在50%以内。我们的工作为柯利牧羊犬提供了系统方法的首个示例，并说明了其用于描述犬Mdr1基因中已知遗传变异影响的用途。此外，我们描述了建立、验证和应用IVIVE-PBPK框架以预测特定犬种体内药物行为的一般工作流程。
