Application of risk assessment and management principles to the extralabel use of drugs in food-producing animals

A risk assessment of the food safety implications of drugs used in food-producing animals is an essential component of the regulatory approval process for products containing these drugs. This ensures that there is negligible risk to human health if these drugs are used according to the instructions that appear on the approved label. A relative paucity of approved products for veterinary species; however, forces veterinarians worldwide to use drugs in an extralabel manner to treat disease and alleviate suffering in animals. In food-producing animals, this may result in residues that are potentially harmful to the human consumer. This review describes how risk assessment principles can be extended to evaluate the risks posed by different classes of extralabel drug use. Risk management practices in the United States and Europe are summarized and contrasted to illustrate the application of these principles.     

Pharmacokinetics of oral meloxicam in ruminant and preruminant calves

The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster (P<0.01) in PRF (0.237±0.0478/h) than RG calves (0.0815±0.0188/h), while absorption in PRG calves (0.153±0.128/h) was not different from other groups. C(max) was lower (P=0.03) in PRF (1.27±0.430 μg/mL) than in PRG calves (2.20±0.467 μg/mL), while C(max) of RG calves (1.95±0.955 μg/mL) was not different from other groups. V/F was higher in PRF calves (365±57 mL/kg) than either PRG (177±63 mL/kg, P<0.01) or RG (232±83 mL/kg, P=0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer.     

Estimation of glomerular filtration rate in healthy cats using single-slice dynamic CT and Patlak plot analysis

Commonly used clinical indicators of renal disease are either insensitive to early dysfunction or have delayed results. Decreased glomerular filtration rate (GFR) indicates renal dysfunction before there is a loss of 50% of functional nephrons. Most tests evaluate global rather than individual kidney function. Dynamic computed tomography (CT) and Patlak plot analysis allows for individual GFR to be tested. Our objectives were to establish a procedure and provide reference values for determination of global GFR in 10 healthy cats using dynamic CT (CTGFR). This method of GFR determination was compared against serum iohexol clearance (SIC). A single CT slice centered on both kidneys and the aorta was acquired every fifth second during and after a bolus injection of iohexol (240 mgI/ml; 300 mgI/kg) for 115 s. Using data from this dynamic acquisition, Patlak plots were obtained, GFR was calculated, and results were compared to global GFR determined by iohexol clearance. The average global CTGFR estimate was 1.84 ml/min x kg (SD = 0.43; range = [1.22, 2.45]). The average global GFR measured using SIC was 2.45 ml/min x kg (SD = 0.58; range = [1.72, 3.69]). GFR measurements estimated by both dynamic CT and SIC were positively associated (estimated Spearman rank correlation coefficient = 0.72; P = 0.0234). The CTGFR method consistently underestimated GFR with a bias of -0.62 (SE = 0.1307) when compared to SIC (P = 0.0011). In healthy cats, CTGFR was capable of determining individual kidney function and appears clinically promising.     

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.     

Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs

To determine the plasma pharmacokinetics of suppository acetaminophen (APAP) in healthy dogs and clinically ill dogs. This prospective study used six healthy client‐owned and 20 clinically ill hospitalized dogs. The healthy dogs were randomized by coin flip to receive APAP orally or as a suppository in crossover study design. Blood samples were collected up to 10 hr after APAP dosing. The hospitalized dogs were administered APAP as a suppository, and blood collected at 2 and 6 hr after dosing. Plasma samples were analyzed by ultra‐performance liquid chromatography with triple quadrupole mass spectrometry. In healthy dogs, oral APAP maximal concentration (C_MAX=2.69 μg/ml) was reached quickly (T_MAX=1.04 hr) and eliminated rapidly (T1/2 = 1.81 hr). Suppository APAP was rapidly, but variably absorbed (C_MAX=0.52 μg/ml T_MAX=0.67 hr) and eliminated (T_1/2 = 3.21 hr). The relative (to oral) fraction of the suppository dose absorbed was 30% (range <1%–67%). In hospitalized ill dogs, the suppository APAP mean plasma concentration at 2 hr and 6 hr was 1.317 μg/ml and 0.283 μg/ml. Nonlinear mixed‐effects modeling did not identify significant covariates affecting variability and was similar to noncompartmental results. Results supported that oral and suppository acetaminophen in healthy and clinical dogs did not reach or sustain concentrations associated with efficacy. Further studies performed on different doses are needed.     

Korrelationen spermabiologischer Merkmale in nativen und aufgetauten Hengstejakulaten unter Berücksichtigung der Transmigration

Inhalt Im Nativsamen von Hengsten ließen sich teilweise sehr enge Korrelationen zwischen den gängigen biologischen Untersuchungsparametern nachweisen, die auch noch nach dem Auftauen der in Makrotüb-Röhrchen nach Martin & Klug (1979a, b) konfektionierten Ejakulate fortbestanden. Bis auf die Beziehung zwischen geschätzter Motilität (%) und dem Prozentsatz an eosin-ungefärbten Samenrellen schwächten sich die Korrelationswerte der übrigen Parameterpaare wie auch die meisten statistischen Signifikanzen nach dem Tiefgefrieren ab. Bemerkenswert war die ausgeprägte positive Abhängigkeit der Motilitätsschätrung im nativen rum aufgetauten Samen desselben Ejakulates, so daß durchschnittlich 60% der ursprünglich vorhandenen Beweglichkeit nach der Kryokonservierung erhalten blieben. Die Transmigrationsrate (TMR, %) nach Holzmann (1987) als ein objektives Kriterium zur Motilitätsbestimmung ließ sich auch bei aufgetautem Hengstsamen anwenden. Contents: Correlations of biological parameters, incl. the transmigrationrate, in native and frozen/thawed equine semen For the characterization of equine semen from native samples as well as from cryopreserved samples according Martin & Klug (1979a, b) the usually tested biological parameters were determinded. Using samples of the same ejaculate the comparison of values revealed that only the relation for estimated motility (%) and estimated viability (%, number of spermatozoa not stained by eosin) were unchanged whereas the correlation of all other tested parameters as well as most of the statistical significances decreased after thawing. A remarkable close positive correlation was determined for estimated motility of native and frozen/thawed spermatozoa. It was found that spermatozoa retained approximately 60% of their native motility after freezing and thawing the ejaculate sample. The determination of the transmigrationsrate (TMR, %) for motility of cryopreserved samples described by Holzmann (1987) showed that this method may be used for stallion spermatozoa, too.     

Mathematical modeling and simulation in animal health – Part II: principles,methods, applications,and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food‐producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food‐producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed‐effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.