Comparative Pharmacokinetic Approaches to Estimating the Pharmacokinetics of Water Medications in Swine

Abstract

ABSTRACT

MASON, SHARON ELIZABETH. Comparative Pharmacokinetic Approaches to Estimating the Pharmacokinetics of Water Medications in Swine. (under the direction of Ronald E. Baynes).

Although water medications have been used in the United States for over 40 years, the pharmacokinetics of these drugs have not been clearly discerned using compartmental pharmacokinetics techniques. No repeated dosing pharmacokinetic studies have been performed on water medications in swine. Therefore we proposed to use three proven techniques in veterinary medicine to model water medications in swine. Non-compartmental modeling, physiologically based pharmacokinetic modeling and population based pharmacokinetic modeling have provide insights in veterinary medicine over the last decade. The application of these techniques to the pharmacokinetics of water medications has never been attempted. Therefore two in vivo studies were performed collect pharmacokinetic information on these drugs and then pharmacokinetic modeling was performed to test these techniques and their application to characterize the disposition characteristics of water medications in swine production settings. In vivo experiments were performed in pigs base on the age and dosing schedules of those treated in commercial production units for tetracycline and sulfamethazine. Non-compartmental analysis techniques were initially applied to these populations. However, due to large variability and unforeseen situations, PBPK and population pharmacokinetic techniques were applied in relevant situations to these medications to provide insight into situations that traditional modeling techniques were unable to elucidate. For sulfamethazine, the use of PBPK modeling proved useful in characterizing the potentially small exposure concentrations that have been documented in the literature for over 25 years. In contrast to sulfamethazine which is chemically very stable, tetracycline has been shown to degrade over time and exposure to high temperatures and sunlight. Ancillary experiments were performed to characterize the bioactivity of tetracycline water medication as dosed in a production setting. Finally population based modeling was applied to data collected from a commercial farm settings to determine factors that may apply to all water medication administration in swine industry. This mixed effect modeling technique was able to provide increased support for the non-compartmental pharmacokinetic findings and to identify factors important to plasma concentrations of medications administered in water. PBPK and population based modeling techniques can be effectively used in modeling water medications in swine. Furthermore, they were able to determine dosing amounts and schedules as well as other factors that affect the concentration of water medications in swine.