A physiologically based pharmacokinetic model linking plasma protein binding interactions with drug disposition

Area of Science:

• Pharmacology
• Veterinary Medicine
• Drug Metabolism

Background:

• Combination drug therapy can increase adverse drug reactions through drug-drug interactions.
• Altered disposition of sulfamethazine (SMZ) with flunixin meglumine (FLU) in swine may increase tissue residues.
• Predictive pharmacokinetic modeling is needed to assess drug interaction consequences.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic model linking plasma protein binding interactions to drug disposition for SMZ and FLU in swine.
• To predict the impact of drug interactions on drug disposition and tissue residues.
• To validate model predictions with in vivo data.

Main Methods:

• Development of a physiologically based pharmacokinetic model.
• Incorporation of plasma protein binding interactions into the model.
• In vivo study to confirm drug interaction and assess tissue disposition.

Main Results:

• The model predicted a sustained decrease in total drug concentration and a temporary increase in free drug concentration.
• An in vivo study confirmed the presence of a drug interaction between SMZ and FLU.
• Neither the model nor the in vivo study indicated clinically significant changes in tissue disposition.

Conclusions:

• A novel modeling approach successfully linked plasma protein binding interactions to drug disposition.
• The developed model can predict the clinical impact of drug interactions.
• This approach can aid in designing dosing regimens and ensuring food supply safety by minimizing tissue residues.