Abstract
A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.
Highlights
The primary objective of population pharmacokinetics (PK) and PK/pharmacodynamic (PD) studies is to help veterinary care providers understand the impact of factors such as age, sex, breed and disease on the drug dose-exposure-response (Lees et al, 2004)
Intrinsic differences in the Lower Limit Of Quantification (LLOQ), accuracy and precision of the various analytical methods used to derive these data can be a significant source of analytical variability
This can be handled by building a residual error function that includes assay performances as a covariate in its model structure (Bonate, 2011)
Summary
The primary objective of population pharmacokinetics (PK) and PK/pharmacodynamic (PD) studies is to help veterinary care providers understand the impact of factors (covariates) such as age, sex, breed and disease on the drug dose-exposure-response (Lees et al, 2004). There is a need to identify the key variables that influence drug disposition and response, and to quantify the magnitude of their effects in veterinary species. An appreciation of the sources of population variability will support efforts to optimize clinical efficacy, minimize safety risks, support dose and drug selection, as well as to identify potential concerns for safety and/or effectiveness in companion or food-producing animals. Nonlinear mixed-effects (NLME) models are a versatile tool for quantifying variability in drug disposition and response as a function of significant patient characteristics (i.e. covariates) (Sheiner et al, 1972). The focus of the present paper is on the concept, definition, and application of NLME models in veterinary sciences
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