The pharmacogenomics of P-glycoprotein and its role in veterinary medicine

Despite advancements in pharmacogenetics in human medicine, the incorporation of pharmacogenetics into veterinary medicine is still in its early stages of development. To date, efforts to understand the pharmacologic impact of genetic variation in veterinary species have largely focused on genes encoding for the membrane transporter, P-glycoprotein (P-gp). The emphasis on the role of P-gp is largely because of safety concerns associated with the use of some macrocyclic lactones in dogs. Because of the body of information available on this topic, we use P-gp as a platform for understanding the importance of population diversity in veterinary medicine. The impact of P-gp on drug pharmacokinetics and pharmacodynamics is considered, along with endogenous and exogenous factors that can modulate P-gp activity. The review includes discussion of how population diversity in P-gp activity can lead to susceptibility to certain diseases or alter patient response to environmental stress or pharmaceutical intervention. In addition, phenotypic diversity also needs to be considered, as demonstrated by the impact of P-gp up-regulation and drug resistance. The aim of this review was to set the stage for further exploration into the impact of genetic and phenotypic variability on drug pharmacokinetics, disease propensity, product formulation and drug response in both companion and food-producing animals.     

Pharmacokinetics and pharmacodynamics of tilmicosin in sheep and cattle

Tilmicosin is a long-acting macrolide antibiotic currently approved for treatment of bovine respiratory disease in the USA. Serum pharmacokinetics of tilmicosin were compared between cattle (major species) and sheep (minor species) after subcutaneous injection in order to evaluate a new potential application of the drug in currently nonapproved species. There were no significant differences in the elimination rates, maximum serum concentrations, half-lives ( t _1/2), areas under the curve ( AUC ), areas under the first-moment curve ( AUMC ), and mean residence times. Volume of distribution ( V d_area) and clearance ( Cl ), when normalized by body weight, were also similar. The only significantly different parameter was time at which maximum drug concentration was reached ( t _max), with sheep having the t _max of 3.9 h, compared to 0.5 h in cattle.
  Although macrolides are considered to be one of the safest anti-infective drugs, adverse cardiovascular effects of several macrolides have been reported. The cardiopulmonary effects of tilmicosin were monitored in healthy adult sheep after receiving a single subcutaneous (s.c.) injection of tilmicosin at the dose of 10 mg/kg, and no significant changes were found. The study indicates that tilmicosin can be used safely and effectively in sheep at the given dose, with no adverse cardiopulmonary effects.     

Considerations for extrapolating in vivo bioequivalence data across species and routes

The purpose of this article is to discuss the numerous species-specific and route-specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species-to-species or route-to-route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across-species and across-route comparisons.     

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

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.     

Patient variation in veterinary medicine--part II--influence of physiological variables

In veterinary medicine, the characterization of a drug's pharmacokinetic properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. In Part I of the series, we focused on the potential influence of disease processes, stress, pregnancy and lactation on drug pharmacokinetics. In this Part II of the series, we consider other covariates, such as gender, heritable traits, age, body composition, and circadian rhythms. The impact of these factors with respect to predicting the relationship between dose and drug exposure characteristics within an animal population is illustrated through the use of Monte Carlo simulations. Ultimately, an appreciation of these potential influences will improve the prediction of situations when dose adjustments may be appropriate.