Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

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.

Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non‐Small Cell Lung Cancer

“…best fit the unfit fluorescence data from the same study. During model building, we attempted to balance our model‐building procedure between model performance (empirical fit) and the underlying biology, an approach often referred to as the middle‐out approach …”

An integrated experimental and physiologically based pharmacokinetic modeling study of penicillin G in heavy sows

“…As the depletion studies were carried out by different labs and with different commercial brands of PPG, the experimental and random variances may be larger than the physiological variability considered in the population PBPK model. The population analysis in current PBPK model did not account for the variabilities between different studies, which could potentially be addressed using the nonlinear mixed‐effect population pharmacokinetic modeling approach (Bon et al, ; Li, Gehring, Lin, & Riviere, ; Mochel et al, ; Mould & Upton, ,; Riviere, Gabrielsson, Fink, & Mochel, ).…”

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

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