Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Abstract

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.

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

“…In human medicine, covariates typically comprise constitutional factors (e.g., bodyweight, age, genotype), and physiological parameters (e.g., markers of renal and/ or hepatic function). In veterinary medicine, additional factors need to be considered, such as hierarchy in pigs (Soraci, Amanto, Tapia, de la Torre, & Toutain, 2014), which influences the ingested amount of drug in medicated feeds, or social behavior manifested by allo-and hetero-licking described in cattle, which is known to affect the drug disposition of pour-on formulations (Toutain, Modric, Bousquet-Mélou, Sallovitz, & Lanusse, 2012). An overview of potential sources of variability in drug disposition kinetics in veterinary medicine is presented in Table 1.…”

The pharmacokinetics of transdermal flunixin meglumine in Holstein calves

“…In this study, cattle were restrained to prevent self-grooming and allo-grooming for the first 4 h postdosing. It has been suggested that the grooming and licking behaviors should be considered when evaluating bioavailability of topical and transdermal drugs (Toutain et al, 2012). However, data presented at the 2014 World Buiatrics Congress reported no difference in absorption of transdermal flunixin if calves were allowed to groom versus not allowed to groom (Crouch et al, 2014).…”

Comparison of bioequivalence study regulatory requirements for human and veterinary drugs

“…This topic is described sparingly, even though the authors of the guideline admit that there are many such formulations. Optimization of such studies still causes many problems, which is emphasized by other authors (Baynes et al, 2012;Toutain et al, 2012). As it is pointed by other authors (Hunter et al, 2012), the current guideline does not solve the problem of optimization of BE studies in relation to premixes.…”