In vitro screening model for compound interactions with human and dairy animal BCRP orthologs.

Orthologs of breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) efflux transmembrane transporter, are present in several species. The list of compounds known to interact with BCRP is growing, and many questions remain concerning species-specific variations in substrate specificity and affinity and the potency of inhibitors. As the most abundant efflux transporter known to be present in the blood-milk barrier, BCRP can increase the elimination of certain xenobiotics to milk, posing a risk for suckling offspring and dairy product consumers. Here we developed a model that can be employed to investigate species-specific differences between BCRP substrates and inhibitors. Membrane vesicles were isolated from transiently transduced human embryonic kidney (HEK) 293 cells, overexpressing BCRP, with human, bovine, caprine, and ovine cDNA sequences. To confirm BCRP transport activity in the transduced cells, D-luciferin efflux was measured and to confirm transport activity in the membrane vesicles, [3H] estrone-3-sulfate ([3H]E1S) influx was measured. We also determined the Michaelis-Menten constant (Km) and Vmax of [3H]E1S for each species. We have developed an in vitro transport model to study differences in compound interactions with BCRP orthologs from milk-producing animal species and humans. BCRP transport activity was demonstrated in the species-specific transduced cells by a reduced accumulation of D-luciferin compared with the control cells, indicating BCRP-mediated efflux of D-luciferin. Functionality of the membrane vesicle model was demonstrated by confirming ATP-dependent transport and by quantifying the kinetic parameters, Km and Vmax for the model substrate [3H]E1S. The values were not significantly different between species for the model substrates tested. This model can be insightful for appropriate inter-species extrapolations and risk assessments of xenobiotics in lactating woman and dairy animals.

Systematic review of physiologically based kinetic lactation models for transfer of xenobiotic compounds to milk.

Lactational elimination has been described mathematically for nearly 50 years. Over 40 published articles, containing >50 physiologically based kinetic (PBK) lactation models were included in the systematic review. These PBK models described the lactational elimination of xenobiotic compounds in humans, rats, mice, and dairy cows and goats. A total of 78 compounds have been modelled, ranging from industrial chemicals, pesticides, to pain medication, antibiotics, and caffeine. Few models included several species or compounds, and models were thus generally not translational or generic. Three dairy cow models mechanistically described the intramammary disposition of pharmaceuticals after intramammary administration, including volume changes caused by milking, while empirically describing the remaining pharmacokinetics. The remaining models were semi- or whole body PBK models, describing long-term exposure of environmental pollutants, or short-term exposure of pharmaceuticals. The absolute majority described the disposition to the mammary gland or milk with perfusion limited compartments, but permeability limited models were available as well. With long-term exposure, models often included changes in milk volume and/or consumption by the offspring, and changes in body weight of offspring. Periodic emptying of the mammary gland, as with feeding or milking, was sparsely applied. Rodent models used similar physiological parameters, while values of physiological parameters applied in human models could range widely. When milk composition was included in the models, it most often included the fat content. The review gives an extensive overview of the applied functions and modelling strategies of PBK lactation models.

PHARMACOKINETICS OF ORAL FLUNIXIN MEGLUMINE, MELOXICAM, OR GABAPENTIN IN THREE BLACK RHINOCEROS (DICEROS BICORNIS).

Pharmacokinetics of single, separate doses of IV flunixin meglumine (1 mg/kg), IV meloxicam (0.5 mg/kg), oral flunixin meglumine (1 mg/kg), oral meloxicam (1 mg/kg), and oral gabapentin (15 mg/kg) in three adult black rhinoceroses (Diceros bicornis) were determined from serial blood collection made over 72 h. The concentration versus time profiles were analyzed for each drug and route in each individual rhinoceros, and individual pharmacokinetic parameters were calculated for each medication administered. Meloxicam had near complete bioavailability in each trial, while flunixin meglumine was generally lower. Oral meloxicam was noted with similar half-life values between all animals (range 9.22-14.52 h) tested, while oral gabapentin had a larger range (range 10.25-24.85 h). Oral flunixin meglumine achieved a lower Cmax (range 170.67-664.38 ng/ml) in this study compared with the mean Cmax (1,207 ng/ml) reported in a similar study in white rhinoceroses (Ceratotherium simum), but some overlap in range of values was noted. Oral flunixin meglumine Tmax (range 1.05-10.78 h) and half-life (range 3.88-14.85 h) values in black rhinoceroses was similar to mean values reported in white rhinoceroses (3 and 8.3 h, respectively).

Co-formulation of ketoprofen with tulathromycin alters pharmacokinetic and pharmacodynamic profile of ketoprofen in cattle.

The current studies aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to establish a PK-PD model for ketoprofen in a new fixed combination product containing tulathromycin (2.5 mg/kg) and ketoprofen (3 mg/kg) to treat bovine respiratory disease associated with pyrexia in cattle. Firstly, the effect of different ketoprofen doses as mono-substance (1, 3, and 6 mg/kg subcutaneous) on lipopolysaccharide-induced fever was evaluated which indicated that rectal temperature reduction lasted longer in the calves receiving 3 and 6 mg/kg ketoprofen. Secondly, the PK profile of the combination product was compared with mono-substance products (3 mg/kg subcutaneous and intramuscular). The PK profile of ketoprofen in the combination product was characterized by longer t1/2 , lower Cmax and increased AUC in comparison with mono-substance products. Due to prolonged ketoprofen exposure in the combination product, the pyrexia reducing effect of the combination product lasted longer in a second lipopolysaccharide challenge study in comparison with mono-substance products. Finally, a PK-PD model for the anti-pyretic effect of ketoprofen was developed based on the data from the different studies. The PK-PD model eliminated the need for additional animal experiments and indicated that a 3 mg/kg ketoprofen dose in the combination product provided optimal efficacy.

The efficacy of subcutaneous slow-release melatonin implants in the prevention of canine flank alopecia recurrence is uncertain: A double-blind, randomized, placebo-controlled study.

BACKGROUND: Canine flank alopecia (CFA) is characterized by seasonally recurring noninflammatory, occasionally hyperpigmented alopecia predominantly in the thoracolumbar area. Previous studies suggest that reduced production of endogenous melatonin may play a role in the pathogenesis of this condition, and placebo-controlled studies on the efficacy of preventative melatonin treatment are lacking. OBJECTIVE: To evaluate the efficacy of subcutaneous slow-release melatonin implants in the prevention of CFA recurrence. ANIMALS: Twenty-one client-owned dogs with a history of CFA were included in the study. MATERIALS AND METHODS: At time (T)0, a general physical and dermatological examination was performed on each dog, blood was collected for serum biochemistry analysis and two skin biopsies were taken from alopecic areas on the nonsedated affected dogs after subcutaneous injection with 2% lidocaine. Dogs with normal blood work and histological results compatible with CFA were included in the study. Participating dogs were randomly assigned to receive either placebo or 18 mg melatonin subcutaneously in the interscapular area, approximately 2 months before expected CFA onset (T1). CFA recurrence was scored qualitatively as complete, ≤50% recurrence, or no recurrence at 5 and 7 months after the intervention (T2 and T3, respectively). RESULTS: At T3, in dogs treated with placebo (nine of 17), the percentages for complete recurrence, ≤50% recurrence and no recurrence were 44%, 0% and 56%, respectively. In dogs treated with melatonin (eight of 17), these percentages were 25%, 50% and 25%, respectively. There were no statistically significant differences in the scores between melatonin-treated dogs and placebo-treated dogs (p = 0.40). In three of eight melatonin-treated dogs, mild transient swelling was observed at the injection site. CONCLUSIONS: This study did not provide evidence that an 18 mg melatonin implant treatment, although well-tolerated, is efficacious in preventing recurrence of CFA in affected dogs.

Pharmacokinetics and bioavailability of tildipirosin following intravenous and subcutaneous administration in horses.

This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection of a single dose at 4 mg/kg of body weight (b.w.). A total of 12 healthy mixed breed horses were used in the study. Horses were monitored for systemic and local adverse effects, and whole blood samples were collected for hematology and plasma biochemistry analysis at time (0) and at 6, 24, and 72 h after drug administration. For PK analysis, blood samples were collected at pre-determined times before and after tildipirosin administration. Plasma concentrations of tildipirosin were determined using ultra-high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). All horses tolerated the i.v. injection of tildipirosin without showing any systemic adverse effects. However, a non-painful, soft swelling appeared at the s.c. injection site in 5 horses (41.7%). On average, tildipirosin reached a maximum plasma concentration (Cmax ) of 1257 ng/ml (geometric mean) between 0.5 and 1.5 h after s.c. administration (Tmax ). The geometric mean values for total body clearance (Cl), the apparent volume of distribution based on the terminal phase (Vz ), and the apparent volume of distribution at steady-state (Vss ) were 0.52 L/kg·h, 22 L/kg, and 10.0 L/kg, respectively. Data collected in this study suggests that tildipirosin can be used safely in horses with caution.

Pharmacokinetics and bioavailability of ketoprofen when compounded with iron dextran for use in nursing piglets.

In Canada, piglets receive analgesia to control pain after surgical castration. There is interest in examining the potential to mix non-steroidal anti-inflammatory drugs with iron dextran prior to injection to minimize piglet handling and labor. The objective of this study was to compare pharmacokinetics and the relative bioavailability of ketoprofen given alone (3.0 mg/kg IM) versus the same dose of ketoprofen mixed with iron dextran (52.8 mg/kg IM) (ketoprofen + iron dextran) before injection in piglets. Piglets 8 to 11 d old were allocated into 2 treatment groups (n = 8/group). Plasma drug concentrations were measured using mass spectrometry at 13 time points after injection. No significant differences were detected between the 2 groups when examining pharmacokinetic parameters (e.g., Cmax, Tmax, AUC) or relative bioavailability for either S- or R-ketoprofen enantiomers (P > 0.05). However, pain control efficacy and food safety studies of these formulations are required to further examine this practice.

Pharmacocinétique et biodisponibilité du kétoprofène lorsque mélangé avec du fer dextran pour utilisation chez les porcelets allaitants. Au Canada, les porcelets reçoivent une analgésie pour diminuer la douleur après une castration chirurgicale. Il y a un intérêt à examiner la possibilité de mélanger des anti-inflammatoires non stéroïdiens avec du fer dextran avant l'injection afin de minimiser la manipulation des porcelets et le travail. L'objectif de cette étude était de comparer la pharmacocinétique et la biodisponibilité relative du kétoprofène administré seul (3,0 mg/kg IM) par rapport à la même dose de kétoprofène mélangé à du fer dextran (52,8 mg/kg IM) (kétoprofène + fer dextran) avant l'injection des porcelets. Des porcelets âgés de 8 à 11 jours ont été répartis en deux groupes de traitement (n = 8/groupe). Les concentrations plasmatiques de médicament ont été mesurées par spectrométrie de masse à 13 moments dans le temps après l'injection. Aucune différence significative n'a été détectée entre les deux groupes lors de l'examen des paramètres pharmacocinétiques (par ex., Cmax, Tmax, AUC) ou de la biodisponibilité relative pour les énantiomères S- ou R-kétoprofène (P > 0,05). Cependant, des études sur l'efficacité de la diminution de la douleur et la sécurité alimentaire de ces formulations sont nécessaires pour examiner de manière plus approfondie cette pratique.(Traduit par Dr Serge Messier).

A study to assess the correlation between plasma, oral fluid and urine concentrations of flunixin meglumine with the tissue residue depletion profile in finishing-age swine.

BACKGROUND: Flunixin meglumine (FM) was investigated for the effectiveness of plasma, oral fluid, and urine concentrations to predict tissue residue depletion profiles in finishing-age swine, along with the potential for untreated pigs to acquire tissue residues following commingled housing with FM-treated pigs. Twenty pigs were housed in groups of three treated and one untreated control. Treated pigs received one 2.2 mg/kg dose of FM intramuscularly. Before treatment and at 1, 3, 6, 12, 24, 36, and 48 h (h) after treatment, plasma samples were taken. At 1, 4, 8, 12 and 16 days (d) post-treatment, necropsy and collection of plasma, urine, oral fluid, muscle, liver, kidney, and injection site samples took place. Analysis of flunixin concentrations using liquid chromatography/tandem mass spectrometry was done. A published physiologically based pharmacokinetic (PBPK) model for flunixin in cattle was extrapolated to swine to simulate the measured data. RESULTS: Plasma concentrations of flunixin were the highest at 1 h post-treatment, ranging from 1534 to 7040 ng/mL, and were less than limit of quantification (LOQ) of 5 ng/mL in all samples on Day 4. Flunixin was detected in the liver and kidney only on Day 1, but was not found 4-16 d post-treatment. Flunixin was either not seen or found less than LOQ in the muscle, with the exception of one sample on Day 16 at a level close to LOQ. Flunixin was found in the urine of untreated pigs after commingled housing with FM-treated pigs. The PBPK model adequately correlated plasma, oral fluid and urine concentrations of flunixin with residue depletion profiles in liver, kidney, and muscle of finishing-age pigs, especially within 24 h after dosing. CONCLUSIONS: Results indicate untreated pigs can be exposed to flunixin by shared housing with FM-treated pigs due to environmental contamination. Plasma and urine samples may serve as less invasive and more easily accessible biological matrices to predict tissue residue statuses of flunixin in pigs at earlier time points (≤24 h) by using a PBPK model.

Oral doxycycline pharmacokinetics: Lambs in comparison with sheep.

The pharmacokinetics of doxycycline was investigated in lactating sheep and lambs after oral administration at a dose of 10 mg/kg. Concentrations in plasma and milk were assayed with HPLC-PDA analysis. Doxycycline penetrates into the milk, and levels (0.38 ± 0.21 µg/ml) were found 0.5 hr after the treatment. The results suggest that the lambs can be exposed to doxycycline by suckling milk from their treated mothers. Population pharmacokinetic analysis showed a positive relationship between age, which reflects the stage of development of rumen function, and clearance. Possible explanations for the observed differences include the undeveloped rumen in lambs, the differences in the feed and liver function as evidenced by the blood biochemical parameters aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which were significantly lower in lambs (62.67 ± 27.83 U/L and 8.50 ± 6.80 U/L) than in sheep (114.33 ± 20.77 U/L and 18.00 ± 3.16 U/L).

Analysis of polymorphisms of canine Cytochrome P 450-CYP2D15.

Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon-intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine.

Pharmacokinetics of imidocarb dipropionate in white-tailed deer (Odocoileus virginianus) after single intramuscular administration.

This study was designed to investigate the pharmacokinetics of imidocarb, a carbanilide derivative, in white-tailed deer (Odocoileus virginianus). The pharmacokinetic properties of a single intramuscular (IM) dose of imidocarb were determined in 10 deer. A single IM injection of 3.0 mg/kg imidocarb dipropionate was administered, and blood samples were collected prior to, and up to 48 hr after imidocarb administration. Plasma imidocarb concentrations were determined by high-performance liquid chromatography with ultraviolet detection. The disposition of plasma imidocarb was best characterized by a two-compartment open model. The mean ± SE maximal imidocarb concentration in deer was 880.78 ± 81.12 ng/ml at 38.63 ± 5.30 min postinjection. The distribution phase had a half-life (t1/2α ) of 25.90 ± 10.21 min, and plasma imidocarb concentration declined with a terminal elimination half-life (t1/2ß ) of 464.06 ± 104.08 min (7.73 ± 1.73 hr). Apparent volume of distribution based on the terminal phase (VZ /F) was 9.20 ± 2.70 L/kg, and apparent total body clearance (Cl/F) was 15.97 ± 1.28 ml min-1  kg-1 .

Application of different pharmacokinetic models to describe and predict pharmacokinetics of voriconazole in magellanic penguins following oral administration.

Aspergillosis is a condition causing serious morbidity and mortality in captive penguins and other bird species. It can be treated with antifungal drugs, such as voriconazole. However, the pharmacokinetics of voriconazole are variable between different animal and bird species. Therefore, the pharmacokinetics of voriconazole were investigated in this study in Magellanic penguins. Pharmacokinetic models were constructed and applied to predict the pharmacokinetics of voriconazole during long-term treatment in Magellanic penguins, since the voriconazole treatment duration in chronic aspergillosis cases can last up to several months. Plasma voriconazole concentration-time data from adult Magellanic penguins (Spheniscus magellanicus; n = 15) following a single oral (PO) dose of either 2.5 mg/kg or 5 mg/kg in a herring in three separate study periods 7-12 months apart were collected. Mean plasma voriconazole concentrations were above the targeted MIC for Aspergillus fumigatus for 2 hr following a single 2.5 mg/kg voriconazole dose while the plasma concentrations exceeded the MIC for least 24 hr following a 5 mg/kg dose. Nonlinear mixed-effects modeling was used to fit two pharmacokinetic models, one with first-order and another with saturable elimination, to the single-dose data. Fits were good for both, as long as dose was included as a covariate for the first-order model so that clearance was lower and the half-life longer for animals receiving the 5 mg/kg dose. Although the single-dose data suggested saturated elimination at higher concentrations, the model with saturable elimination did not predict plasma voriconazole concentrations well for a clinical aspergillosis case receiving long-term treatment, possibly because of induction of metabolizing enzymes with chronic exposure. Pharmacokinetic models should accurately predict plasma drug concentrations for different dosage regimens in order to be applicable in the field. Future studies should focus on determining clearance at steady-state to be able to refine the pharmacokinetic models presented here and improve model performance for long-term oral voriconazole administration in Magellanic penguins.

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

Penicillin G is widely used in food-producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal-derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow-derived meat products.

Alfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics.

OBJECTIVE: To evaluate the cardiovascular effects, pharmacokinetic (PK) data and recovery characteristics of an alfaxalone constant rate infusion (CRI) of different duration in dogs at manufacturer's recommended dose rate. STUDY DESIGN: Experimental, prospective, randomized, crossover study. ANIMALS: Six intact female Beagles. METHODS: Following an intravenous alfaxalone bolus (3 mg kg-1), anaesthesia was maintained using an alfaxalone CRI at 0.15 mg kg-1 minute-1 for 90 (short CRI) or 180 minutes (long CRI). Venous blood samples were collected to determine the PK profile. Cardiovascular variables and recovery characteristics were evaluated. Recovery was scored on a scale ranging from 0, excellent to 4, bad. A mixed-model statistical approach was used to compare the cardiovascular parameters (global α = 0.05). An analysis of variance was performed to compare PK parameters and recovery times between treatments. RESULTS: No significant difference was noted between protocols for any PK parameter. Volume of distribution at steady state (935.74 ± 170.25 versus 1119.15 ± 190.65 mL kg-1), elimination half-life (12 ± 2 versus 13 ± 3 minutes), clearance from the central compartment (26.02 ± 4.41 versus 27.74 ± 5.65 mL kg-1 minute-1) and intercompartmental clearance (8.47 ± 4.06 versus 12.58 ± 7.03 mL kg-1 minute-1) were comparable for short CRI and long CRI. Cardiovascular variables remained within physiological limits. Mechanical ventilation was necessary (short CRI: n = 1, long CRI: n = 4). The manufacturer's recommended dose rate resulted in a light plane of anaesthesia. No significant differences in recovery times and scores were observed between treatments. The quality of recovery was scored as very poor with both protocols. CONCLUSIONS AND CLINICAL RELEVANCE: PK data were similar between long and short infusions of alfaxalone at the manufacturer's recommended dose, with acceptable cardiovascular conditions. Nevertheless, both protocols resulted in a superficial plane of general anaesthesia with poor recovery characteristics.

Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer.

Aspergillosis is a fungal infection that primarily affects the respiratory tract. Amphotericin B has broad antifungal activity and is commonly used to treat aspergillosis, a fungal pneumonia that is a common sequela in oiled waterfowl as well as other birds in wildlife rehabilitation. Pharmacokinetic parameters of nebulized amphotericin B in an avian model have been reported, but those of direct intratracheal delivery have yet to be established. The objective of this study was to evaluate if a single 3 mg/kg dose of liposomal amphotericin B delivered intratracheally using a commercial atomizer would achieve plasma and lung tissue concentrations exceeding targeted minimum inhibitory concentrations (MIC) for Aspergillus species in adult mallard ducks (Anas platyrhynchos). Following intratracheal delivery, amphotericin B was present in lung parenchyma at concentrations above the targeted MIC of 1 µg/g for up to 9 days post-administration; however, distribution of the drug was uneven, with the majority of the drug concentrated in one lung lobe. Concentrations in the contralateral lung lobe and the kidneys were above the targeted MIC 1 day after administration but declined exponentially with a half-life of approximately 2 days. Plasma concentrations were never above the targeted MIC. Histological examination of the trachea, bronchi, lungs, heart, liver, and kidneys did not reveal any toxic changes. Using a commercial atomizer, intratracheal delivery of amphotericin B at 3 mg/kg resulted in lung parenchyma concentrations above 1 µg/ml with no discernable systemic effects. Further studies to establish a system of drug delivery to both sides of the pulmonary parenchyma need to be performed, and the efficacy of this treatment for disease prevention remains to be determined.

Drug residues in poultry meat: A literature review of commonly used veterinary antibacterials and anthelmintics used in poultry.

Poultry meat is widely consumed throughout the world and production practices often include the administration of pharmaceutical products. When appropriate, extra-label drug use of medications is necessary, but scientifically derived drug withdrawal intervals must be observed so that poultry meat is not contaminated with drug residues which could pose health risks to consumers. Over the past decade, there has been increased advocacy for judicious use of antimicrobial drugs for treating food animals. Judicious use of medications is commonly referred to as practices that reduce antibiotic resistance, but also includes residue avoidance. In that light, many investigators have performed scientific studies and have published estimated pharmacokinetic parameters for veterinary medications used in commercial avian species. This manuscript is a review of medication classes that have been studied in poultry (mostly chickens) with an emphasis on drug residue depletion in poultry meat.

Population variability in animal health: Influence on dose-exposure-response relationships: Part II: Modelling and simulation.

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session on the influence of population variability on dose-exposure-response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals.

Single-Dose Pharmacokinetics of Piperacillin/Tazobactam in Hispaniolan Amazon Parrots ( Amazona ventralis ).

To determine the pharmacokinetics of piperacillin/tazobactam in Hispaniolan Amazon parrots ( Amazona ventralis ), 8 healthy adult parrots of both sexes were used in a 2-part study. In a pilot study, piperacillin (87 mg/kg) in combination with tazobactam (11 mg/kg) was administered intramuscularly (IM) to 2 birds, and blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after administration. Based on the results obtained, a main study was done in which piperacillin/tazobactam was administered at 2 different doses. In 3 birds, the initial dose of piperacillin (87 mg/kg)/tazobactam (11 mg/kg) IM was administered, and in 3 birds, the dose was doubled to piperacillin (174 mg/kg)/tazobactam (22 mg/kg) IM. In all 6 birds, blood samples were obtained at 0, 5, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, and 4 hours after administration. Quantification of plasma piperacillin and tazobactam concentrations was determined by validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis. After intramuscular administration, the mean ± standard error values of T1/2 (h) was 0.52 ± 0.05 and 0.32 ± 0.07, Tmax (h) was 0.28 ± 0.09 and 0.25 ± 0.10, Cmax (µg/mL) was 86.34 ± 20.62 and 9.03 ± 2.88, and Cmax/dose was 0.99 ± 0.24 and 0.83 ± 0.26 for piperacillin (87 mg/kg) and tazobactam (11 mg/kg), respectively. When the doses were doubled, the T1/2 (h) was 0.65 ± 0.08 and 0.34 ± 0.02, Tmax (h) was 0.28 ± 0.12 and 0.14 ± 0.06, Cmax (µg/mL) was 233.0 ± 6.08 and 22.13 ± 2.35, and Cmax/dose was 1.34 ± 0.03 and 1.02 ± 0.11 for piperacillin and tazobactam, respectively. Results indicate that piperacillin is rapidly absorbed and reaches high initial concentrations; however, it is also rapidly eliminated in the Hispaniolan Amazon parrot, and tazobactam has similar pharmacokinetics as piperacillin. Administration of piperacillin at 87 mg/kg IM q3-4h is recommended for this species to control infections attributed to susceptible bacteria with a minimum inhibitory concentration of ≤4 µg/mL.

Plasma Concentrations of Fentanyl Achieved With Transdermal Application in Chickens.

Providing appropriate analgesia is an important concern in any species. Fentanyl, a µ-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying breeds for 72 hours. Repeated blood samples were collected from the birds to assess time-concentration of fentanyl and norfentanyl in plasma, as assayed by liquid chromatography-mass spectrometry, throughout patch application and for 48 hours after patch removal. Compartmental modeling was used to characterize the elimination profiles. Evaluation as a large bolus, followed by slower elimination rates over the remaining time, best fit the data as a one-compartment open model. Although maximum plasma fentanyl concentrations varied substantially by individual birds, chickens trended into 2 general groups of maximum plasma concentration, clearance, and volume of distribution, which was attributed to absorption variability. For all birds, harmonic mean of elimination half-life was 7.2 ± 3.7 hours and showed less individual variation than the other pharmacokinetic parameters. Because the application of transdermal fentanyl patches in the chickens achieved plasma fentanyl concentrations considered therapeutic in people, this approach could provide an additional analgesic option for avian patients.

Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach.

BACKGROUND: Extra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance. RESULTS: All animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle. CONCLUSIONS: The results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time.