Search

Summary: Background: Tiludronate is a bisphosphonate drug marketed to treat different bone conditions in horses. Objectives: The goal of this study was to measure the plasma concentrations of tiludronate in a population of race and sport horses under field conditions, and using pharmacokinetic population modelling, to estimate detection times for doping control. Study design: Prospective cohort. Methods: This study was conducted under field conditions on 39 race or sport horses diagnosed with bone conditions based on a lameness examination and treated with tiludronate. Each horse received 1 mg/kg of tiludronate (Tildren®) intravenously (i.v.). Blood samples (from 1 to 4 per horse with a total of 93 samples) were collected around 10, 20, 30, 40 and 50 days after tiludronate administration. Tiludronate was quantified by HPLC/ESI‐MSn. Tiludronate concentrations were analysed using nonlinear mixed‐effects modelling (population approach). Monte Carlo simulations were then used to compute a prediction interval to estimate the corresponding quantile of horses predicted to have concentrations below some potential screening limits. Results: This study highlighted pharmacokinetic differences between healthy experimental horses and the population of horses being treated in the field as well as the effect of level of training on plasma tiludronate. Different detection times were computed corresponding to different possible screening limits. Main limitations: The number of horses in each group was limited, and the specific disease being treated with tiludronate is unknown. Conclusions: This population pharmacokinetic study on tiludronate will enable racing and other sports authorities to provide a detection time reflecting field conditions for the medication control of tiludronate. More generally, our study design and the data modelling serve as an example of how to generate detection times directly from the target horse population rather than from experimental horses. [ABSTRACT FROM AUTHOR]

The article presents a study that demonstrates the use of nonlinear mixed effects (NLME) to characterize and quantify variability in veterinary pharmacokinetics. It highlights the use of the approach to characterize the sources of variability in drug disposition and response used in both companion and food-producing animals. It also concludes the advantages of the NLME as a useful tool in estimating withdrawal times (WT) of approved animal drug products and optimizing dosing schedules.

A calf tissue cage model was used to study the pharmacokinetics (PK) and pharmacodynamics (PD) of oxytetracycline in serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids. After intramuscular administration, the PK was characterized by a long mean residence time of 28.3 hr. Based on minimum inhibitory concentrations (MICs) for six isolates each of Mannheimia haemolytica and Pasteurella multocida, measured in serum, integration of in vivo PK and in vitro PD data established area under serum concentration-time curve (AUC0-∞)/MIC ratios of 30.0 and 24.3 hr for M. haemolytica and P. multocida, respectively. Corresponding AUC0-∞/MIC ratios based on MICs in broth were 656 and 745 hr, respectively. PK-PD modelling of in vitro bacterial time-kill curves for oxytetracycline in serum established mean AUC0-24 hr/MIC ratios for 3log10 decrease in bacterial count of 27.5 hr ( M. haemolytica) and 60.9 hr ( P. multocida). Monte Carlo simulations predicted target attainment rate (TAR) dosages. Based on the potency of oxytetracycline in serum, the predicted 50% TAR single doses required to achieve a bacteriostatic action covering 48-hr periods were 197 mg/kg ( M. haemolytica) and 314 mg/kg ( P. multocida), respectively, against susceptible populations. Dosages based on the potency of oxytetracycline in broth were 25- and 27-fold lower (7.8 and 11.5 mg/kg) for M. haemolytica and P. multocida, respectively. [ABSTRACT FROM AUTHOR]

The fates of sulfadimethoxine ( SDM) for different routes of administration were investigated in muscle tissue of giant freshwater prawns, Macrobrachium rosenbergii, following either intramuscular (i.m.) or gavage administration at a dosage of 50 mg/kg body weight (b.w.). The depletion patterns of SDM were also examined after medicated feed treatment at the feeding concentration of 10 g/kg of feed twice a day at a rate of 1% of total b.w. for five consecutive days. The concentration of SDM in prawn muscle tissue was measured using a high-performance liquid chromatography ( HPLC) equipped with ultraviolet detector. Noncompartmental analyses were used to estimate basic pharmacokinetic parameters for the i.m. and gavage data, while a population model was developed to analyze the entire data set including the feed group. Using the Monte Carlo simulations, the withdrawal times ( WT) for the orally administered SDM in feed supplement were determined. Maximum concentration of SDM was significantly higher in the i.m. than in the gavage group, and the area under the curve ( AUC) value for relative bioavailability following gavage administration was 25.6%. Using Monte Carlo simulation, for a maximum residue limit ( MRL) of 0.1 μg/g, the WT for muscle after oral administration of SDM in feed was estimated to be 67 h, while for a MRL of 0.2 μg/g, the WT was estimated to be of 54 h. [ABSTRACT FROM AUTHOR]

The antimicrobial properties of tulathromycin were investigated for M. haemolytica and P. multocida. Three in vitro indices of antimicrobial activity, minimum inhibitory concentration ( MIC), minimum bactericidal concentration ( MBC) and time-kill curves, were established for six isolates of each organism. Each index was measured in two growth media: Mueller-Hinton broth ( MHB) and calf serum. It was shown that MICs and MBCs were markedly lower in serum than in MHB. MHB:serum ratios for MIC were 47:1 ( M. haemolytica) and 53:1 ( P. multocida). For both serum and MHB, adjustment of pH led to greater potency at alkaline compared to acid pH. Tulathromycin MIC was influenced by size of inoculum count, being 4.0- to 7.7-fold greater for high compared to low initial counts. It was concluded that for the purpose of determining dosages for therapeutic use, pharmacodynamic data for tulathromycin should be derived in biological fluids such as serum. It is hypothesized that in vitro measurement of MIC in broth, conducted according to internationally recommended standards, may be misleading as a basis for estimating the in vivo potency of tulathromycin. [ABSTRACT FROM AUTHOR]

The pharmacokinetic ( PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations ( MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic ( PD) index ( AUC(0-24 h)/ MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/ PD cutoffs required for the development of antimicrobial susceptibility testing ( AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation ( MCC). The computation predicted a target attainment rate ( TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/ PD concepts. [ABSTRACT FROM AUTHOR]

The antimicrobial properties of amoxicillin were determined for the bovine respiratory tract pathogens, Mannheima haemolytica and Pasteurella multocida. Minimum inhibitory concentration ( MIC), minimum bactericidal concentration ( MBC) and time-kill curves were established. Pharmacokinetic ( PK)/pharmacodynamic ( PD) modelling of the time-kill data, based on the sigmoidal Emax equation, generated parameters for three levels of efficacy, namely bacteriostatic, bactericidal (3log10 reduction) and 4log10 reduction in bacterial counts. For these levels, mean AUC(0-24 h)/ MIC serum values for M. haemolytica were 29.1, 57.3 and 71.5 h, respectively, and corresponding values for P. multocida were 28.1, 44.9 and 59.5 h. Amoxicillin PK was determined in calf serum, inflamed (exudate) and noninflamed (transudate) tissue cage fluids, after intramuscular administration of a depot formulation at a dosage of 15 mg/kg. Mean residence times were 16.5 (serum), 29.6 (exudate) and 29.0 h (transudate). Based on serum MICs, integration of in vivo PK and in vitro PD data established maximum concentration ( Cmax)/ MIC ratios of 13.9:1 and 25.2:1, area under concentration-time curve ( AUC0-∞)/ MIC ratios of 179 and 325 h and T> MIC of 40.3 and 57.6 h for P. multocida and M. haemolytica, respectively. Monte Carlo simulations for a 90% target attainment rate predicted single dose to achieve bacteriostatic and bactericidal actions over 48 h of 17.7 and 28.3 mg/kg ( M. haemolytica) and 17.7 and 34.9 mg/kg ( P. multocida). [ABSTRACT FROM AUTHOR]

Mavacoxib is a novel nonsteroidal anti-inflammatory drug ( NSAID), with a preferential action on the cyclooxygenase ( COX)-2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic ( PK) profile comprises very slow body clearance, long elimination half-life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis ( OA). In OA dogs, mavacoxib exhibits a much longer terminal half-life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics ( PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX-1 and COX-2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies. [ABSTRACT FROM AUTHOR]

A reply to the letter to the editor is presented in response to the article "The consequences of generic marketing on antibiotic consumption and the spread of microbial resistance: the need for new antibiotics" by P. L. Toutain and A. Bousquet-Melou.

Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs ( NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic ( PK/ PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three-period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin ( PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/ PD modelling. S(+) ketoprofen clearance scaled by bioavailability ( CL/F) was 0.114 L/kg/h (elimination half-life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half-life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivo IC50 COX-1/ IC50 COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a global challenge that impacts both human and veterinary health care. The resilience of microbes is reflected in their ability to adapt and survive in spite of our best efforts to constrain their infectious capabilities. As science advances, many of the mechanisms for microbial survival and resistance element transfer have been identified. During the 2012 meeting of Antimicrobial Agents in Veterinary Medicine ( AAVM), experts provided insights on such issues as use vs. resistance, the available tools for supporting appropriate drug use, the importance of meeting the therapeutic needs within the domestic animal health care, and the requirements associated with food safety and food security. This report aims to provide a summary of the presentations and discussions occurring during the 2012 AAVM with the goal of stimulating future discussions and enhancing the opportunity to establish creative and sustainable solutions that will guarantee the availability of an effective therapeutic arsenal for veterinary species. [ABSTRACT FROM AUTHOR]

The author reflects on the potential toxicity for individuals that consume horse meat containing phenylbutazone and its metabolites. He cites various equine-related studies including pharmacodynamics, pharmacokinetics, carcinogenicity, and general toxicological profile. The author clarifies that the use of phenylbutazone is allowed for equine use but it is banned for use in food producing animals.

In both human and veterinary medicine, it has been shown that flooding the market with different generics and/or 'me-too' branded drugs has increased overall antibiotic consumption correlating with the emergence and spread of bacterial resistance to antibiotics. Another possible undesirable consequence of the promotion of generics is the promotion of an economic incentive that encourages the use of old drug products with very poor oral bioavailability, marketed with historical dosage regimens and extensively excreted in the environment. What veterinary medicine rather needs is new innovative and 'ecofriendly' antibiotics to actually enforce a more prudent use of antibiotics. For a pharmaceutical company, generics are inexpensive to manufacture and on a short-term basis, the generic market is very appealing. However, on a long-term basis, this marketing orientation provides a disincentive to the development of new and innovative products that will be required to meet the therapeutic needs of the veterinary community while being consistent with public health concerns. Indeed, for veterinary medicine, the key issue surrounding antibiotics is public health. It is the opinion of the authors that veterinary antibiotics and/or veterinary drug formulations should be innovative in terms of selectivity (no or minimal impact on the commensal gut flora), biodegradable (with minimal environmental disruption), and more expensive, with a strictly regulated market rather than unselective, cheap, and freely available drugs. [ABSTRACT FROM AUTHOR]

Veterinary therapeutics, based on the art of Materia Medica, has been practised for countless centuries, but the science of veterinary pharmacology is of very recent origin. This review traces the contribution of Materia Medica to veterinary therapeutics from the Egyptian period through to the Age of Enlightenment. The first tentative steps in the development of the science of veterinary pharmacology were taken in the 18th century, but it was not until the mid 20th century that the science replaced the art of Materia Medica. This review traces the 20th century developments in veterinary pharmacology, with emphasis on the explosion of knowledge in the 35 year period to 2010. The range of factors which have influenced the current status of the discipline are reviewed. Future developments are considered from the perspectives of what might be regarded as desirable and those innovations that might be anticipated. We end with words of encouragement for young colleagues intent upon pursuing a career in veterinary pharmacology [ABSTRACT FROM AUTHOR]

Toutain, P.-L., Modric, S., Bousquet-Mélou, A., Sallovitz, J. M., Lanusse, C. Should licking behavior be considered in the bioavailability evaluation of transdermal products? J. vet. Pharmacol. Therap. 35 (Suppl. 1), 39-43. 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. [ABSTRACT FROM AUTHOR]

Hunter, R. P., Lees, P., Concordet, D., Toutain, P.-L. Establishing bioequivalence of veterinary premixes (Type A medicated articles). J. vet. Pharmacol. Therap. 35 (Suppl. 1), 53-63. [ABSTRACT FROM AUTHOR]

Baynes, R., Riviere, J., Franz, T., Monteiro-Riviere, N., Lehman, P., Peyrou, M., Toutain, P.-L. Challenges obtaining a biowaiver for topical veterinary dosage forms. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 103-114. Obtaining a biowaiver for topical drugs used in veterinary species faces many of the same challenges associated with human topicals. However, the skin of domestic animals varies anatomically and biochemically and experimental approaches to assess bioequivalence (BE) in veterinary species have challenges that are not often encountered with human skin. This is especially the situation with locally acting drugs. The focus of this paper is to address several of the challenges associated with (i) determining the BE of these locally acting drugs and (ii) critically examine the current technological advances that can act as a surrogate for clinical trials. [ABSTRACT FROM AUTHOR]

Lees, P., Hunter, R. P., Reeves, P. T., Toutain, P. L. Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 17-29. Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed. [ABSTRACT FROM AUTHOR]

Pelligand, L., King, J. N., Toutain, P. L., Elliott, J., Lees, P. Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation. J. vet. Pharmacol. Therap. 35, 19-32. Robenacoxib is a novel nonsteroidal anti-inflammatory drug developed for use in cats. It is a highly selective COX-2 inhibitor. Results from previous feline studies showed that, despite a short half-life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib's pharmacokinetics and its ex vivo and in vivo selectivity for COX-1 and COX-2 using serum TxB2 and exudate PGE2 as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54-0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX-1 in blood was transient, occurring only at high concentrations, but inhibition of COX-2 in exudate persisted to 24 h. The potency ratio (IC50 COX-1: IC50 COX-2) was 171:1, and slopes of the concentration-effect relationship were 1.36 and 1.12 for COX-1 and COX-2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once-daily administration. [ABSTRACT FROM AUTHOR]

The chiral pharmacokinetics and pharmacodynamics of ketoprofen were investigated in a placebo-controlled study in piglets after intramuscular administration of 6 mg/ kg racemic ketoprofen. The absorption half-lives of both enantiomers were short, and S-ketoprofen predominated over R-ketoprofen in plasma. A kaolin-induced inflammation model was used to evaluate the antiinflammatory, antipyretic and analgesic effects of ketoprofen. Skin temperatures increased after the kaolin injection, but the effect of ketoprofen was small. No significant antipyretic effects could be detected, but body temperatures tended to beμower in the ketoprofen-treated piglets. Mechanical nociceptive threshold testing was used to evaluate the analgesic effects. The piglets in the ketoprofentreated group had significantly higher mechanical nociceptive thresholds compared to the piglets in the placebo group for 12-24 h following the treatment. Pharmacokinetic / pharmacodynamic modelling of the results from the mechanical nociceptive threshold testing gave a median IC50 for S-ketoprofen of 26.7μg / mL and an IC50 for R-ketoprofen of 1.6μg / mL. This indicates that Rketoprofen is a more potent analgesic than S-ketoprofen in piglets. Estimated ED50 for racemic ketoprofen was 2.5 mg/ kg. [ABSTRACT FROM AUTHOR]

In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/ kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.μg·h/ mL for serum, 12.1μg·h/ mL for inflamed tissue cage fluid (exudate) and 9.6μg·h/ mL for noninflamed tissue cage fluid (transudate). Values of Cmax were 1.84, 0.35 and 0.31μg / mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid Emax equation provided AUC24 h / MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC90 value of 0.24μg / mL, a dose of 2.6 mg/ kg for MB and 2.19 mg/ kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/ kg. [ABSTRACT FROM AUTHOR]

Summary Reason for performing study: For legitimate medications, veterinarians must advise the owners or trainers of horses on appropriate withholding times after a treatment, to avoid the risk of incurring a positive drug test. Objective: To explore the safety span to select that a veterinarian may extrapolate a tailored withdrawal time (WT) from a generic detection time (DT) as published by the European Horserace Scientific Liaison Committee (EHSLC). Methods: Using Monte Carlo simulations, it was shown that for a low variability of pharmacokinetic parameters (CV = 20%), an uncertainty span of about 40% may be selected to transform a mean DT into a WT (i.e. WT = 1.4 DT), which covers 90% of the horse population. In contrast for a highly variable drug (CV = 40%), an uncertainty factor of about 2.1-2.2 needs to be selected, i.e. a WT that is twice the DT. Results: The relative impact of the different factors of variability on the final WT was documented by a so-called sensitivity analysis. It was shown that the parameters that have the greatest influence on the value of a DT are those that control the terminal half-life of the drug disposition. In contrast, parameters controlling the level of urine (or plasma) concentrations (i.e. the actual administered dose, the urine-to-plasma ratio and the bioavailability) collectively have a minimal influence on the DT. Conclusions and potential relevance: In practice, this means that the main sources of uncertainty are of biological origin and cannot be reduced by any managerial options. The influence of the number of experimental horses that are used by EHSLC to establish a DT was shown that with the standard EHLSC protocol of 6 horses, half of the trials lead to a proposed DT that is equal to or higher than the population 90th percentile. Increasing the number of investigated horses to 8 and 10 would increase this last probability to 85 and 90%, respectively. [ABSTRACT FROM AUTHOR]

Summary Reasons for performing study: Equine antidoping rules were established to prevent a horse's performance being altered after the administration of prohibited substances, including approved drugs used for legitimate treatment. Veterinarians have to advise owners or trainers on appropriate withholding times to guarantee that their horses may safely compete after drug administration. In order to propose tailored withdrawal times, several horse organisations released detection time (DT) values, for the main veterinary drugs used in horses. One of the possible limits to the information provided by published DTs in horses is the fact that they are determined from classic pharmacokinetic studies performed at rest under laboratory conditions. In field conditions, training and exercise programmes may have an influence on drug elimination. Methods: Dexamethasone (DMX) and phenylbutazone (PBZ) have been quantified in plasma and urine after solid phase extraction. The kinetic disposition of DXM (8 μg/kg) and PBZ (8 mg/kg) administered by i.v. route in 8 horses, was investigated in rest conditions and during a standardised 3 h test exercise according to a cross-over design. Objectives: The aim of the present study was to compare the kinetic disposition of 2 test drugs, DMX and PBZ in rest vs. exercising conditions. Results: It was shown in 8 horses that a sustained 3 h of mild exercise slightly decreased the plasma clearance of both drugs (about 25% for DXM and 37% for PBZ) and this is mainly explained by the significant decrease of the corresponding hepatic clearance. In addition, as the volume of distribution was correlatively decreased, the plasma terminal half-life, which is a hybrid parameter of plasma clearance and volume of distribution, remains unchanged overall. Conclusion and potential relevance: Establishing DTs or withdrawal times (WTs) are relevant as plasma and urine half-lives, but not clearance, are the main determinants of DT length. Veterinarians may realistically decide upon a WT for a legitimate drug based on the corresponding DT obtained under resting conditions providing this drug has a low hepatic extraction ratio and a safety margin is added to allow for all possible sources of variability. [ABSTRACT FROM AUTHOR]

Robenacoxib is a new nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration–time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX-1 and COX-2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B2 provided a marker of both COX-1 and COX-2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC50 were 28.9 (16.4–51.1) μm (COX-1) and 0.058 (0.010–0.340) μm (COX-2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX-1:COX-2) were 502.3 (IC50/IC50), 451.6 (IC95/IC95) and 17.05 (IC20/IC80). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX-1 and 90% inhibition of COX-2. [ABSTRACT FROM AUTHOR]

This study investigated the analgesic, anti-inflammatory and antipyretic efficacy of the new COX-2 selective inhibitor robenacoxib in the cat and established pharmacodynamic (PD) parameters for these effects. Robenacoxib, at a dosage of 2 mg/kg administered subcutaneously, was evaluated in a kaolin-induced paw inflammation model in 10 cats, using both clinically relevant endpoints (lameness scoring, locomotion tests) and other indicators of inflammation (body and skin temperature, thermal pain threshold) to establish its pharmacological profile. A pharmacokinetic/pharmacodynamic (PK/PD) modelling approach, based on indirect response models, was used to describe the time course and magnitude of the responses to robenacoxib. All endpoints demonstrated good responsiveness to robenacoxib administration and both the magnitude and time courses of responses were well described by the indirect pharmacodynamic response models. Pharmacokinetic and clinically relevant pharmacodynamic parameters were used to simulate dosage regimens that will assist the planning of clinical trials and the selection of an optimal dosage regimen for robenacoxib in the cat. [ABSTRACT FROM AUTHOR]

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t1/2 < 1 min), whilst COX-2 binding was slowly reversible ( t1/2 = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2–30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40–0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall–Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF1α concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs. [ABSTRACT FROM AUTHOR]

Moxidectin is a long-acting anthelmintic drug for which little is known about its kinetic behaviour in dogs and its oral absolute bioavailability has never been reported. We studied the pharmacokinetics of moxidectin in dogs, with a special emphasis on oral bioavailability and the influence of lipid co-administration, by using a semi-simultaneous method of administration. Ten Beagle dogs were dosed orally and then intravenously (i.v.) with 0.2 mg/kg moxidectin. The oral application was conducted with or without corn oil co-administration. Moxidectin concentration–time profiles in plasma were analysed using a compartmental modelling approach, designed to fit the oral and i.v. kinetic disposition curves simultaneously. In contrast to what happens in other species, our study indicates that the bioavailability of orally given moxidectin in dogs is nearly total (90.2 ± 7.4%), and is not enhanced by lipid co-administration. The clearance, the volume of distribution, the mean residence time and the terminal half-life were similar to what was already described for other species. Finally our trial suggests that the body condition (degree of obesity) is likely to be a major determinant of moxidectin kinetics in dogs because of its modulation of the volume of distribution that indirectly controls the terminal half-life of the drug. [ABSTRACT FROM AUTHOR]

A letter to the editor reporting the meclofenamic acid urine excretion profile in horses studied in different bedding conditions is presented.

Objective Antimicrobial resistance is not only here, it is here to stay and it poses major threats to the effective use of antimicrobial drugs in humans and other animals. Nevertheless, a defeatist attitude is not acceptable. There is much that can and must be done to retard or prevent the emergence and spread of resistance. Clinicians and scientists from many disciplines have roles to play in combating resistance and we veterinary pharmacologists arguably have the most important role of all. As Schentag (1996) indicated 10 years ago, ‘‘The design of appropriate dosage regimens may be the single most important contribution of clinical pharmacology to the resistance problem’’. However, progress has not been rapid and as recently as 2003 Drusano commented, ‘‘One area in which there is little investigation is the use of proper dosing to help prevent emergence of resistance’’ and, again in 2005, Drusano et al. commented ‘‘little attention has been focussed on delineating the correct dose to suppress the amplification of less susceptible mutant bacterial sub-populations’’. In this Workshop we address, with the help of internationally recognised authorities, antimicrobial resistance in veterinary medicine, from the perspectives of basic mechanisms, epidemiology and pre-clinical and population PK-PD modelling in dosage design. In addition, we review prudent use, clinical aspects and the contribution of regulatory efforts to minimise the selection of resistant microorganisms. [ABSTRACT FROM AUTHOR]

Giraudel, J. M., Diquelou, A., Lees, P., Toutain, P. L. Development and validation of a new model of inflammation in the cat and selection of surrogate endpoints for testing anti-inflammatory drugs. J. vet. Pharmacol. Therap. 28, 275–285. In laboratory animals many models of inflammation have been developed for preclinical evaluation of the pharmacological profiles of nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, in species of veterinary interest, including the cat, NSAIDs have been studied mainly using dose-titration or dose-confirmation studies in clinical subjects. This is due to the scarcity of appropriate animal models and to the associated lack of quantitative validated endpoints describing the magnitude and time course of drug response. Determination of pharmacokinetic/pharmacodynamic (PK/PD) relationships provides a powerful approach for the selection of effective and safe dosage regimens. In this study, a paw inflammation model in the cat was developed for the preclinical evaluation of NSAIDs using PK/PD modelling. Subcutaneous injection of 500 mg kaolin in the paw produced a well-defined and reproducible inflammatory response that lasted 4–5 days. Several endpoints were assessed for their clinical relevance and for their metrological performance (accuracy and reproducibility). Body temperature, lameness scoring, locomotion tests and possibly skin temperature were the most appropriate endpoints for testing the antipyretic, analgesic and anti-inflammatory effects of NSAIDs in the cat. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Bousquet-Mélou, A. Plasma clearance.J. vet. Pharmacol. Therap.27, 415–425.Plasma (total, systemic...) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances. Plasma clearance (a volume per time, i.e. a flow) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration level. The interpretation of plasma clearance and inter-species comparisons are made easier by computing the overall body extraction ratio (from 0 to 1), which is the ratio of the body clearance divided by cardiac output. Plasma clearance is the most important pharmacokinetic parameter because it is the only one which controls the overall drug exposure (for a given bioavailability) and it is the parameter which allows computation of the dosage required to maintain an average steady-state plasma concentration. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Bousquet-Mélou, A. Plasma terminal half-life.J. vet. Pharmacol. Therap.27, 427–439.Terminal plasma half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose. When the process of absorption is not a limiting factor, half-life is a hybrid parameter controlled by plasma clearance and extent of distribution. In contrast, when the process of absorption is a limiting factor, the terminal half-life reflects rate and extent of absorption and not the elimination process (flip-flop pharmacokinetics). The terminal half-life is especially relevant to multiple dosing regimens, because it controls the degree of drug accumulation, concentration fluctuations and the time taken to reach equilibrium. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Lefèbvre, H. P. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships for angiotensin-converting enzyme inhibitors.J. vet. Pharmacol. Therap.27, 515–525.The pharmacokinetic (PK) properties and the pharmacokinetic/pharmacodynamic (PK/PD) relationships for the angiotensin-converting enzyme (ACE) inhibitors (ACEIs), such as enalaprilat, benazeprilat, imidaprilat and ramiprilat, differ from those of conventional drugs. This is because of their immediate and saturable binding to an ACE pool which is partly circulating (and contributing to the measured plasma concentration), and partly noncirculating (tissular), being anchored to the endothelium of vessels and not measurable by the analytical technique. A physiologically based model is required to allow appropriate interpretation of the different phases of the disposition curve of ACEI. The protracted terminal phase observed for all ACEIs is not a conventional elimination phase but a phase dependent on ACEI dissociation from ACE. In contrast, the phase which reflects ACEI elimination (and which is interpreted as a distribution phase for a conventional drug) has a short half-life, thus explaining the absence of drug accumulation during repeated dosing and mild kidney failure. ACE inhibition is the surrogate endpoint generally selected for establishing a PK/PD relationship and for simulating dosage regimen scenarios in order to decide on the appropriate dosage regimen for ACEIs. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Bousquet-Mélou, A. Volumes of distribution.J. vet. Pharmacol. Therap.27, 441–453.Volumes of distribution are proportionality constants between total amount of drug in the body and plasma concentrations. As snapshot plasma drug concentrations may be measured in different conditions (at equilibrium, under pseudo-equilibrium condition,...), several volumes of distribution have been defined. The two most relevant are the volume of distribution at equilibrium (Vss), and the volume of distribution during pseudo-equilibrium (Varea). Volumes of distribution are used to compute a loading dose (Vss) or the residual amount of drug in the body knowing plasma concentrations (Varea). Volume of distribution may be interpreted in terms of drug distribution having recourse to physiological models involving drug binding to plasma and tissues. Volumes of distribution should be determined early in drug development programmes and those having a large volume of distribution may be selected to obtain a long terminal half-life even for drugs having a relatively high clearance. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Bousquet-Mélou, A. Bioavailability and its assessment.J. vet. Pharmacol. Therap.27, 455–466.Bioavailability is a key pharmacokinetic parameter which expresses the proportion of a drug administered by any nonvascular route that gains access to the systemic circulation. Presented in this review are the different approaches to measurement of bioavailability (absolute and relative), including the case in which intravenous administration is impossible. The rate of drug absorption is also discussed with special emphasis on the possible difficulties encountered usingCmax andTmax or curve fitting to evaluate the rate of drug absorption. [ABSTRACT FROM AUTHOR]

Toutain, P. L., Lees, P. Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine.J. vet. Pharmacol. Therap.27, 467–477.In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration–effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities. [ABSTRACT FROM AUTHOR]

Monnoyer, S., Guyonnet, J., Toutain, P. L. A preclinical pharmacokinetic/pharmacodynamic approach to determine a dose of GnRH, for treatment of ovarian follicular cyst in cattle.J. vet. Pharmacol. Therap.27,527–535.The objective of this study was to explore the value of a preclinical PK/PD approach to determine a gonadotropin-releasing hormone (GnRH) dose in cows using the pituitary LH response as a surrogate endpoint.Using an indirect effect model with stimulation of the LH entry rate, thein vivobasic pharmacodynamic parameters of GnRH were determined. The EC50 of GnRH was 51 ± 16 pg/mL, the EC50 being the GnRH plasma concentration able to produce 50% of the maximum possible stimulation (Smax) of the hypophysis (Smax = 48 ± 13). From individual PK/PD parameters, the ED50 of GnRH, i.e. the estimated dose of GnRH required to determine half the maximum possible stimulating effect on LH release, was calculated to 62 μg/h per cow. Using the PK/PD model, the GnRH dose required to achieve a selected breakpoint value of 5 ng/mL for maximum LH concentration (surrogate value for LH concentration predicting clinical efficacy for cystic conditions), was 52 ± 18 μg and for a standard GnRH dose of 100 μg, the mean maximum plasma LH concentration predicted by the model was 7.22 ± 0.98 ng/mL. [ABSTRACT FROM AUTHOR]

Lees, P., Giraudel, J., Landoni, M. F., Toutain P. L. PK–PD integration and PK–PD modelling of nonsteroidal anti-inflammatory drugs: principles and applications in veterinary pharmacology.J. vet. Pharmacol. Therap.27, 491–502.Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK–PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog.In the PK–PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily)in vivoin the same investigation and then modelledin silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidalEmax (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK–PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data forS-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight.PK–PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK–PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration–effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat. [ABSTRACT FROM AUTHOR]

Lees, P., Landoni, M. F., Giraudel, J., Toutain, P. L. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest.J. vet. Pharmacol. Therap.27, 479–490.This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It isnotintended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK–PD integration and PK–PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate.The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole bloodin vitroassays are used to investigate quantitatively the three key PD parameters (efficacy, potency and sensitivity) for NSAID inhibition of COX isoforms, providing data on COX-1:COX-2 inhibition ratios. Limited published data point to species differences in NSAID-induced COX inhibition, for both potency and potency ratios. Members of the 2-arylpropionate sub-groups of NSAIDs exist in two enantiomeric forms [R-(−) andS-(+)] and are licensed as racemic mixtures. For these drugs there are marked enantiomeric differences in PK and PD properties of individual drugs in a given species, as well as important species differences in both PK and PD properties. [ABSTRACT FROM AUTHOR]

Lefebvre, H. P., Toutain, P. L. Angiotensin-converting enzyme inhibitors in the therapy of renal diseases.J. vet. Pharmacol. Therap.27,265–281.Renal diseases, especially chronic renal failure (CRF), are common in canine and feline medicine. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in these conditions in the development of renal lesions and the progression of kidney dysfunction. Angiotensin-converting enzyme inhibitors (ACEI) are currently considered as the most efficient agents in therapeutic strategies. The benefit of an ACEI treatment can be explained by at least three mechanisms: ACEI limit systemic and glomerular capillary hypertension, have an antiproteinuric effect, and retard the development of glomerulosclerosis and tubulointerstitial lesions. These effects have been studied in dogs and cats, and there is now some evidence to support the recommendation of ACEI therapy in dogs and cats with CRF. Nevertheless the prescription of ACEI in such patients should take into account the potential influence of renal impairment on ACEI disposition, and adverse effects on the renal function itself (especially hypotension and acute reductions in glomerular filtration rate). The risk of drug interaction with diuretics, nonsteroidal anti-inflammatory drugs and anesthetics, should not be overestimated. Furthermore, hypotension may occur in patients on a low sodium diet. [ABSTRACT FROM AUTHOR]

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14 C-benazeprilat and oral 14 C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (V c = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t 1/2 ∼ 1.0 h; Cl ∼ 0.125 L/kg/h), elimination being principally biliary (∼85%) rather than urinary (∼15%). Nevertheless, inhibition of ACE was long-lasting (t 1/2 16–23 h) due to high affinity binding of benazeprilat to ACE (K d ∼ 3.5 mmol/L, IC50 ∼ 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action). [ABSTRACT FROM AUTHOR]

Discusses the distinction between the free fraction of a drug in plasma and its free plasma concentration, as the terms are used in veterinary pharmacology. Factors that control each of the two variables; Consequences for the two variables of competitive drug interaction or alteration of protein binding concentration.

Summary Marbofloxacin is a fluoroquinolone antibiotic expected to be effective in the treatment of infections involving Gram-negative and some Gram-positive bacteria in horses. In order to design a rational dosage regimen for the substance in horses, the pharmacokinetic properties of marbofloxacin were investigated in 6 horses after i.v., subcutaneous and oral administration of a single dose of 2 mg/kg bwt and the minimal inhibitory concentrations (MIC) assessed forbacteria isolated from equine infectious pathologies. The clearance of marbofloxacin was mean ± s.d. 0.25 ± 0.05 l/kg/h and the terminal half-life 7.56 ± 1.99 h. The marbofloxacin absolute bioavailabilities after subcutaneous and oral administration were 98 ± 11% and 62 ± 8%, respectively. The MIC required to inhibit 90% of isolates (MIC [ABSTRACT FROM AUTHOR]

The mean (sd) concentration of plasma 20β-dihydrocortisol in 126 scrapie.affected sheep was 5.5 (7.0) ng/ml compared with 1.1 (0.7) ng/ml in 52 healthy sheep. The mean (sd) concentration of creatinine in the urine of 93 scrapie.affected sheep was 2.43 (1.56) pg/ml compared with 0.94 (0.86) μg/mI in 49 healthy sheep and 1.10 (0.95) μg/ml in 25 sheep with other diseases. These discriminant analyses carried out on healthy and scrapie.affected sheep showed that plasma 20β-dihydrocortisol and urinary creatinine were the best predictors of the disease, and classified correctly 98 per cent of healthy sheep and 82 per cent of scrapie.affected sheep. [ABSTRACT FROM PUBLISHER]

The pharmacokinetic properties and in vitro potency of nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) were investigated in 8 or 10 dogs after intravenous (i.v.), intramuscular (i.m.) and oral (single and multiple dose) administrations at the nominal dose of 5 mg/kg. After i.v. administration, the plasma clearance was 15.3 ± 4.2 mL/kg/h, the steady-state volume of distribution was low (0.18 ± 0.011 L/kg) and the elimination half-life was 8.5 ± 2.1 h. After i.m. administration, the terminal half-life was 14.0 ± 5.3 h indicating a slow process of absorption with a maximum plasma concentration (6.1 ± 1.5 μg/mL) at 10.9 ± 2.1 h postadministration and the systemic bioavailability was 69 ± 22%. After oral administration in fasted dogs, the maximal plasma concentration (10.1 ± 2.7 μg/mL) was observed 6.1 ± 1.6 h after drug administration, the plasma half-life was 6.2 ± 1.9 h and the mean bioavailability was 47 ± 12%. After daily oral administrations for 5 days, the average plasma concentration during the fifth dosage interval was 8.1 ± 2.9 μg/mL and the overall bioavailability was 58 ± 16%. The mean accumulation ratio was 1.27 ± 0.4. In vitro nimesulide inhibitory potencies for cyclooxygenase (COX)-1 and COX-2 isoenzymes were determined using a whole blood assay. Canine clotting blood was used to test for inhibition of COX-1 activity and whole blood stimulated by lipopolysaccharide (LPS) was used to test for inhibition of COX-2 activity. The inhibitory concentration (IC50) for inhibition of COX-2 and COX-1 were 1.6 ± 0.4 μM (0.49 ± 0.12 μg/mL) and 20.3 ± 2.8 μM (6.3 ± 0.86 μg/mL) giving a nimesulide COX-1/COX-2 ratio of 12.99 ± 3.41. It was concluded that at the currently recommended dosage regimen (5 mg/kg), the plasma concentration totally inhibits COX-2 and partly inhibits COX-1 isoenzyme. [ABSTRACT FROM AUTHOR]

The present experiment was designed to determine a dosage regimen (dose, interval of administration) in the dog for nimesulide, a nonsteroidal anti-inflammatory drug with in vitro selectivity for the inhibition of cyclo-oxygenase 2 (Cox-2), using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The PK/PD results were compared with those obtained using a classical dose titration study. In the PK/PD experiment, 11 dogs were subjected to Freund’s adjuvant arthritis characterized by permanent hyperthermia. Nimesulide (5 mg/kg, oral route) was tested during the secondary phase of the inflammatory response. In the dose titration study, nimesulide (0, 3, 6 and 9 mg/kg, oral route) was tested in eight other dogs using a reversible urate crystal arthritis in a 4-period crossover design. Different PD endpoints (including lameness assessed by force plate and hyperthermia) were regularly measured during the PK/PD experiment, and plasma samples were obtained to determine the plasma nimesulide concentration. The data were modeled using an indirect effect model. The IC50 of nimesulide for lameness was 6.26 ± 3.01 μg/mL, which was significantly higher than the EC50 value obtained for antipyretic effect (2.72 ± 1.29 μg/mL). The ED50 estimated from the classical dose titration study were 1.34 mg/kg (lameness) and 3.0 mg/kg (skin temperature). The PK/PD parameters were used to simulate different dosage regimens (dose, interval of administration). The antipyretic and anti-inflammatory effects were calculated from the model for the recommended dosage regimen (5 mg/kg/24 h). It was apparent from this approach, that this dosage regimen enabled 76% of the theoretical maximal drug efficacy to be obtained for pyresis and 43% for lameness. It was concluded from the comparison of in vivo and in vitro IC50, that nimesulide is a potent NSAID for which some Cox-1 inhibition is required to obtain clinically relevant efficacy. [ABSTRACT FROM AUTHOR]

Summary The aim of this study was to document the 24 h urinary Cortisol concentrations during a rest day and a day that included prolonged exercise. The influence of exercise on disposition (plasma, urine) of a dose of Cortisol (1 mg/kg) was also assessed. Six adult saddle horses were used. In one experiment, urinary Cortisol elimination rates were measured during rest and prolonged exercise (56 km, 12 km/h) corresponding to about 50% of the V̇O [ABSTRACT FROM AUTHOR]

Summary The pharmacokinetics of tolfenamic acid were studied in five ponies after an intravenous (iv) administration (2 mg/kg bodyweight [bwt]) and in four horses after an oral administration (30 mg/kg bwt) of tolfenamic acid. The plasma levels were determined by high pressure liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). For the iv administration, a three-compartment model was used to represent the plasma concentration-time curve of the drug. The elimination half-life of the compound was 6.1 ± 1.5 h, the total body clearance was 72.4 ± 16.7 ml/kg bwt/h and the steady-state volume of distribution 0.32 ± 0.11 litres/kg bwt. For the oral administration, absorbtion was delayed with a mean lag-time to absorption of 32 ± 28 mins. The peak plasma concentration 11.1 ± 0.69 μg/ml was observed after a highly variable delay ranging from 1.9 to 6.5 h post administration. The terminal half-life (4.2 ± 0.48 h) was very similar; to that obtained after iv administration. Tolfenamic acid could not be detected in equine plasma with the described analytical methods more than 48 h after drug administration. [ABSTRACT FROM AUTHOR]