Enhanced magnetic resonance imaging assessment of tumor microvasculature

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The study of the pharmacokinetic characteristics of drugs is one o f the initial steps in the pre-clinicai development of therapeutic compounds for humans and animals, and one that has proven essential in the design o f appropriate dosage regimens in the target species. In this context, traditional pharmacokinetic studies have proven incapable o f 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. In the case of food animal patients, this is further compounded by the necessity o f adjusting withdrawal times according to the clinical characteristics o f particular subpopulations, in order to avoid violative residue concentrations. A new technique, population pharmacokinetics, has been applied in humans to overcome these difficulties. Population pharmacokinetics can be defined as a study of the basic features o f 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. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number o f samples were obtained per individual, such as those in late stage human clinical trials. 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. The exploratory nature o f this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc) and drug disposition and/or effect. Similarly, the utilization o f these techniques in the clinical research phases of drug development optimize the determination o f efficacy and safety of drugs. In light o f these developments, and given the absolute lack o f research on the population pharmacokinetics of drugs in veterinary medicine, studies were conducted to test the hypothesis that clinical characteristics o f animals can be used within the frame of mixed-effects modeling techniques in order to develop population predictive models.

These models would be applied to the adjustment of dosage regimens in individual patients, of withdrawal times for label and extralabel drug use, and to extrapolate dosage regimens across species based on allometric relationships between species characteristics (e.g. typical body weight) and in vivo measured pharmacokinetic analysis. The initial study evaluated the population pharmacokinetics of gentamicin in foals and adult horses, using retrospective data obtained from the clinical records o f horses treated at the North Carolina State Veterinary Teaching Hospital for a period o f eight years. A total o f 62 horses were included in the study, with an average of 4.8 samples per horse. Detailed history of dosage, sample collection times, and selected pathophysiologic variables were recorded for each patient. Two-compartment models, with and without clinical covariates, were fit to the data. 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 model was validated with an entirely new subpopulation of animals, and dosage regimens were designed for different individuals according their clinical characteristics.