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.

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.

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.

Patient variation in veterinary medicine: part I. Influence of altered physiological states.

In veterinary medicine, the characterization of a drug's pharmacokinetic (PK) properties is generally based upon data that are derived from studies that employ small groups of young healthy animals, often of a single breed. These are also the data from which population predictions are often generated to forecast drug exposure characteristics in the target population under clinical conditions of use. In veterinary medicine, it is rare to find information on the covariates that can influence drug exposure characteristics. Therefore, it is important to recognize some of the factors that can alter the outcome of PK studies and therefore potentially alter the pharmacological response. Some of these factors are easily identified, such as breed, gender, age, and body weight. Others are less obvious, such as disease, heritable traits, and environmental factors. This manuscript provides an overview of the various stressors (such as disease, inflammation, pregnancy, and lactation) that can substantially alter drug PK. Part II of this series provides an overview of the potential impact of physiological variables such as age, weight, and heritable traits, on drug PK. Ultimately, failure to identify appropriate covariates can lead to substantial error when predicting the dose-exposure relationship within a population.

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.

Effect of respiratory tract disease on pharmacokinetics of tilmicosin in rats.

BACKGROUND AND PURPOSE: In rats, murine respiratory mycoplasmosis is caused by Mycoplasma pulmonis. Tilmicosin, a macrolide antibiotic, has good tissue penetration and reaches high concentration in the lungs. Therefore, a model for studying the effects of disease on pharmacokinetics of tilmicosin was developed, using LEW rats. METHODS: Seventy-two LEW rats were assigned at random to two groups: one group was inoculated with M. pulmonis, and the other served as an uninoculated control group. On postinoculation day 31, all rats received a single dose of tilmicosin (20 mg/kg of body weight, subcutaneously). RESULTS: Concentration of tilmicosin in the lungs of both groups of rats was significantly higher than serum tilmicosin concentration at all times. Infected rats had significantly higher lung tilmicosin concentration than did noninfected rats. No correlation was found between pH of the lungs and tilmicosin concentration in the lungs in either treatment group, nor did treatment have any effect on pH of the muscle. CONCLUSION: Tilmicosin accumulates in the lungs, and infection/inflammation further improves its tissue penetration.

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 (t1/2), areas under the curve (AUC), areas under the first-moment curve (AUMC), and mean residence times. Volume of distribution (Vd(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 (tmax), with sheep having the tmax 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.

Effects of Plasmodium berghei (Apicomplexa) on Nippostrongylus brasiliensis (Nematoda) infection in the mouse, Mus musculus.

Ova and free oxygen radical production and relative peripheral eosinophilia during single and concurrent infections in mice with P. berghei and N. brasiliensis were investigated. Prolonged helminth patent periods indicate that Nippostrongylus self-cure in concurrently infected mice was suppressed. Differential white blood cell determinations showed that the relative number of peripheral blood eosinophils steadily increased (P < or = 0.05) during a Nippostrongylus infection when compared to noninfected controls. Eosinophil levels in mice singly infected with P. berghei or concurrently infected with both parasites did not differ significantly from those of controls suggesting a suppression by Plasmodium of Nippostrongylus-induced eosinophilia. Generation of intestinal free oxygen radicals was indirectly assessed using the Thiobarbituric Acid Assay to measure malondialdehyde (MDA). Intestinal MDA levels were significantly elevated (P < or = 0.05) during single Plasmodium infections as well as concurrent infections while there was no change in MDA production during single Nippostrongylus infections. These results suggest suppression by Plasmodium of the immune response to Nippostrongylus, allowing prolonged patent periods. They also suggest that eosinophils play a role in self-cure while free oxygen radicals do not.

Absence of typical Nippostrongylus brasiliensis self-cure in putative BALB/c mice.

Rejection of Nippostrongylus brasiliensis in mice typically occurs by 14 days postinfection (PI). We report here on a putative BALB/c mouse strain from the University of Texas at El Paso (UTEP) animal colony that did not exhibit a normal pattern of self-cure. Following subcutaneous inoculation with approximately 500 third-stage larvae of N. brasiliensis, the parasite was present in substantial numbers in UTEP BALB/c mice on days 21 and 28 PI and in low numbers through day 70 PI regardless of host sex. Normal self-cure was observed using identical techniques in 2 other BALB/c strains and a CFW strain. Hence, the UTEP BALB/c mouse provides a unique tool to examine the immune response to N. brasiliensis.