A Bottom-up Approach for Mutant and Wild Type Collies Using Physiologically Based Pharmacokinetic (PBPK) Modeling: A...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Veterinary Pharmacology
• Computational Biology

Background:

• Loperamide is a substrate for P-glycoprotein (P-gp), encoded by the multidrug resistance 1 (Mdr1) gene.
• Genetic variations in the Mdr1 gene, such as in the Collie breed, can significantly alter drug pharmacokinetics.
• Accurate prediction of drug behavior in specific canine breeds is crucial for safe and effective therapeutic use.

Purpose of the Study:

• To develop a bottom-up physiologically based pharmacokinetic (PBPK) model for predicting loperamide pharmacokinetics in Collies.
• To incorporate in vitro-to-in vivo extrapolation (IVIVE) techniques for predicting in vivo drug exposure.
• To evaluate the model's performance in both wild-type (WT) and Mdr1-deficient (Mu, Δ-Mdr1) Collies.

Main Methods:

• Development of a breed-specific whole-body PBPK model for Collies using published physiological data.
• Application of in vitro-to-in vivo extrapolation (IVIVE) to predict loperamide absorption, distribution, metabolism, and elimination (ADME).
• Utilized the Simcyp Animal Simulator for loperamide IVIVE-PBPK modeling and simulation.

Main Results:

• The developed PBPK model successfully captured observed plasma concentration-versus-time profiles for loperamide in both WT and Mu Collies.
• Model predictions for Area Under the Curve (AUC) and maximal plasma concentration (Cmax) showed good agreement with observed values.
• Predicted Cmax values were within ±25% of observed values for 67% of WT dog doses, and AUC predictions were within 50% for all Mu dog doses.

Conclusions:

• This study presents the first systematic approach for developing a Collie-specific PBPK model to predict loperamide pharmacokinetics.
• The model effectively illustrates the impact of the canine Mdr1 genetic variation on drug disposition.
• The established IVIVE-PBPK framework provides a general workflow for predicting in vivo drug behavior in specific canine breeds.