Population pharmacokinetic modeling of the serum disposition, interspecies extrapolation and residue depletion of gentamicin and oxytetracycline

The study of the pharmacokinetic characteristics of drugs is one of the initial steps in the pre-clinical development of therapeutic compounds for humans and animals, and one that has proven essential in the design of appropriate dosage regimens in the target species. Traditional pharmacokinetic studies have proven incapable of directly identifying subpopulations whose disposition features differ significantly from the average individual. These subpopulations may require adjustments in their dosage regimens that have to be tailored to their clinical characteristics.;A new technique, population pharmacokinetics, has already been applied in humans. Population pharmacokinetics is the study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability.;Population pharmacokinetics is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. This situation is commonly encountered in veterinary medicine, clinical patients or population of food animals treated with drugs cannot be subject to extensive blood sampling, due to ethical and/or economical reasons. This technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc) and drug disposition and/or effect.;Studies were conducted to test the hypothesis that clinical characteristics of animals can be used within the frame of mixed-effects modeling techniques in order to develop population predictive models.;The initial study evaluated the population pharmacokinetics of gentamicin in foals and adult horses. In the best predictive model, clearance was linearly correlated to body weight and serum creatinine concentration, and volume was linearly related to body weight. The interindividual coefficients of variability for these parameters as well as the intraindividual variability were explicitly estimated.;The interspecies population study was conducted using pharmacokinetic data on gentamicin and oxytetracycline. Interspecies pharmacokinetic models for both drugs were obtained that allowed prediction of serum concentration across species. In the case of oxytetracycline, the variable of interest was body weight. The gentamicin model predictions were validated with retrospective data and those for oxytetracycline were validated with both retrospective and experimental data.;The tissue depletion study addressed the necessity of developing a consistent approach to the establishment of extralabel withdrawal times and a population pharmacokinetic-based strategy to validate those estimates. An entirely new theoretical approach named Extralabel Withdrawal-Interval Estimator (EWE) Algorithm was developed, which proved useful for establishing extralabel withdrawal times based on the drug label information and a minimum amount of pharmacokinetic data. A population pharmacokinetic strategy was also developed that served the purposes of both validating the EWE estimates and directly establishing withdrawal times.;These population pharmacokinetics studies demonstrated that mixed effects modeling can be used in veterinary medicine to define subpopulation characteristics in animals that account for variability that is not explained in traditional pharmacokinetic studies. This allows for a better prediction of the drug concentration in serum and tissue of animals, after drug treatment Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. We conclude that population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labeling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530). (Abstract shortened by UMI.)...