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- Author or Editor: Pierre-Louis Toutain x
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Abstract
Objective—To determine pharmacokinetic-pharmacodynamic (PK-PD) relationships and dose effects for meloxicam in horses and to propose a suitable dosage for use in clinical studies.
Animals—6 adult horses.
Procedure—The study was conducted by use of a randomized, Latin-square design. Arthritis was induced in the right carpal joint of each horse by administration of Freund's complete adjuvant. Various dosages of meloxicam (0, 0.25, 0.5, 1.0, and 2.0 mg/kg, IV) were then administered. Validated endpoints including stride length and overall clinical lameness score (scale of 0 to 20) were used to assess the effect of meloxicam. The dose-effect relationship was quantified by use of a maximum possible effect (Emax) model.
Results—For stride length (expressed as a relative percentage increase from control values), the median effective dose (ED50) was 0.120 mg/kg for an Emax of 11.15%. For clinical lameness score (expressed as an absolute increase from the control value), the ED50 was 0.265 mg/kg for an Emax of 9.16 units. The PK-PD analysis allowed calculation of a median effective concentration of 130 ng/mL for stride length and 195 ng/mL for lameness score. Use of the Emax model predicted a maximal possible increase in effect of 19.5% for stride length and 13.91 units for lameness score. For stride length and lameness score, the Hill coefficient (slope) was extremely high, which suggested a steep dose-effect relationship.
Conclusions and Clinical Relevance—Results of this study suggest that meloxicam is a potent anti-inflammatory drug in horses. A dosage of 0.6 mg/kg/d would be appropriate for use in a clinical study. (Am J Vet Res 2004;65:1533–1541)
Abstract
Objective—To evaluate, by use of population pharmacokinetics, the disposition of marbofloxacin in the aqueous humor after IV administration in dogs and identify its potential usefulness in the prophylaxis and treatment of intraocular infection.
Animals—63 dogs.
Methods—Dogs received a single dose of marbofloxacin (2 mg · kg–1, IV) at various time intervals before cataract surgery. Aqueous humor and blood samples were collected at the beginning of surgery. Marbofloxacin concentrations were measured by high-pressure liquid chromatography. Data were analyzed with a nonlinear mixed-effect model and, by use of population pharmacokinetic parameters, the time course of aqueous humor concentration was simulated for single doses of 3, 4, and 5.5 mg · kg–1IV. Pharmacodynamic surrogate markers and measured aqueous humor concentrations were used to predict in vivo antimicrobial activity.
Results—A maximum marbofloxacin concentration of 0.41 ± 0.17 µg·mL–1 was reached in the aqueous humor 3.5 hours after IV administration. In the postdistributive phase, marbofloxacin disappeared from aqueous humor with a half-life of 780 minutes. The percentage penetration into the aqueous humor was 38%. Predictors of antimicrobial effects of marbofloxacin (2 mg · kg–1, IV) indicated that growth of the enterobacteriaceae and certain staphylococcal species would be inhibited in the aqueous humor. Marbofloxacin administered IV at a dose of 5.5 mg · kg–1 would be predicted to inhibit growth of Pseudomonas aeruginosa and all strains of staphylococci but would not eradicate streptococcal infections.
Conclusions and Clinical Relevance—Marbofloxacin administered IV can penetrate the aqueous humor of canine eyes and may be suitable for prophylaxis or treatment of certain anterior chamber infections. (Am J Vet Res 2003;64:889–893)
Abstract
Objective—To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2.
Animals—10 cats.
Procedure—COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant.
Results—These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme.
Conclusions and Clinical Relevance—In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing. (Am J Vet Res 2005;66:700–709)
Abstract
Objective—To compare penetration of IV administered marbofloxacin in intraocular fluids of healthy and inflamed eyes in rabbits with endotoxin-induced endophthalmitis.
Animals—35 pigmented rabbits.
Procedures—Endophthalmitis was induced in the right eye via intravitreal administration of Escherichia coli endotoxin. The left eye was a control eye. After 24 hours, a single dose of marbofloxacin (4 mg/kg, IV) was administered. Groups of rabbits (n = 5/group) were euthanized 0.5, 1, 2, 4, 6, 10, and 18 hours later, and blood and ocular fluids were collected. Marbofloxacin concentrations were determined via reverse-phase high-performance liquid chromatography, and pharmacokinetic analysis of the data was performed with a mono-compartmental model.
Results—Mean area under the aqueous concentration-time curve was significantly lower in control eyes (1.64 ± 0.07 μg•h/mL) than in inflamed eyes (3.31 ± 0.11 μg•h/mL). Similarly, drug penetration into aqueous humor was 33% and 65% for control eyes and inflamed eyes, respectively. Mean area under the vitreous humor concentration-time curve for control eyes(1.75 ± 0.05 μg•h/mL) was significantly less than for inflamed eyes (2.39 ± 0.16 μg•h/mL). In the vitreous humor, corresponding penetrations were 34% and 47%, respectively.
Conclusions and Clinical Relevance—Penetration of marbofloxacin into the aqueous and vitreous humor after IV administration was significantly enhanced by intraocular inflammation, suggesting a role for this antimicrobial in the prophylaxis or treatment of bacterial endophthalmitis caused by susceptible pathogens.
Abstract
Objective—To assess the effects of moderate exercise on plasma creatine kinase (CK) pharmacokinetics and to estimate exercise-induced muscle damage in dogs.
Animals—6 untrained adult Beagles.
Procedure—The study was divided into 3 phases. In phase 1, dogs ran for 1 hour at a speed of 9 km/h, and samples were used to determine the area under the plasma CK activity versus time curve (AUC) induced by exercise. In phases 2 and 3, pharmacokinetics of CK were calculated in dogs during exercise and at rest, respectively. Values for AUC and plasma clearance (Cl) were used to estimate muscle damage.
Results—At rest, values for Cl, steady-state volume of distribution (Vdss), and mean retention time (MRT) were 0.32 ± 0.02 ml/kg of body weight/min, 57 ± 17.3 ml/kg, and 3.0 ± 0.57 h, respectively. During exercise, Cl decreased significantly (0.26 ± 0.03 ml/kg/min), MRT increased significantly, (4.4 ± 0.97 h), and Vdss remained unchanged. Peak of plasma CK activity (151 ± 58.8 U/L) was observed 3 hours after completion of exercise. Estimated equivalent amount of muscle corresponding to the quantity of CK released was 41 ± 29.3 mg/kg.
Conclusion and Clinical Relevance—These results revealed that exercise had a minor effect on CK disposition and that the equivalent amount of muscle damaged by moderate exercise was negligible. This study illustrates the relevance for use of the minimally invasive and quantitative pharmacokinetic approach when estimating muscle damage. (Am J Vet Res 2001;62:1375–1380)
Abstract
Objective—To determine pharmacokinetic parameters for meloxicam, a nonsteroidal anti-inflammatory drug, in horses.
Animals—8 healthy horses.
Procedure—In the first phase of the study, horses were administered meloxicam once in accordance with a 2 × 2 crossover design (IV or PO drug administration; horses fed or not fed). The second phase used a multiple-dose regimen (daily oral administration of meloxicam for 14 days), with meloxicam administered at the recommended dosage (0.6 mg/kg). Plasma and urine concentrations of meloxicam were measured by use of validated methods with a limit of quantification of 10 ng/mL for plasma and 20 ng/mL for urine.
Results—Plasma clearance was low (mean ± SD; 34 ± 0.5 mL/kg/h), steady-state volume of distribution was limited (0.12 ± 0.018 L/kg), and terminal half-life was 8.54 ± 3.02 hours. After oral administration, bioavailability was nearly total regardless of feeding status (98 ± 12% in fed horses and 85 ± 19% in nonfed horses). During once-daily administration for 14 days, we did not detect drug accumulation in the plasma. Meloxicam was eliminated via the urine with a urine-to-plasma concentration that ranged from 13 to 18. Concentrations were detected for a relatively short period (3 days) after administration of the final daily dose.
Conclusions and Clinical Relevance—Results of this study support once-daily administration of meloxicam regardless of the feeding status of a horse and suggest a period of at least 3 days before urine concentrations of meloxicam reach concentrations that could be used in drug control programs. (Am J Vet Res 2004;65:1542–1547)
Abstract
Objective—To measure florfenicol concentrations in ovine tear fluid after IM and SC administration and determine minimum inhibitory concentrations (MICs) of florfenicol against field isolates of Mycoplasma organisms potentially involved in infectious keratoconjunctivitis.
Animals—9 healthy adult Lacaune ewes.
Procedures—Animals received an IM and SC administration of florfenicol (20 mg/kg) in a 2-way crossover design. Samples of blood and tear fluid were collected before and for 24 hours after administration. Concentrations of florfenicol in plasma and tear fluid were measured via high-performance liquid chromatography. The MIC of florfenicol for various Mycoplasma strains cultured from sheep and goats was determined via an agar dilution method.
Results—Mean florfenicol concentration in tear fluid for the 24-hour period was significantly higher after IM administration (0.70 μg/mL) than after SC administration (0.22 μg/mL) and was maintained for a longer duration. The lacrimal fluid-to-plasma concentration ratio was not different between the 2 routes of administration, with mean values of 40.2% and 32.5% after IM and SC administration, respectively. The MIC for Mycoplasma agalactiae, Mycoplasma conjunctivae, and Mycoplasma mycoides isolates ranged from 0.5 to 8 μg of florfenicol/mL. Two strains of M agalactiae could be considered resistant to florfenicol.
Conclusions and Clinical Relevance—Florfenicol readily penetrated the preocular tear fluid of sheep after IM and SC administration. For both routes of administration, doses > 20 mg/kg would be necessary to achieve tear fluid concentrations of florfenicol greater than the MICs for most strains of Mycoplasma organisms.
Abstract
Objective—To determine pharmacodynamic cutoffs with pharmacokinetic-pharmacodynamic principles and Monte Carlo simulation (MCS) for use of amoxicillin in pigs to set interpretive criteria for antimicrobial susceptibility testing.
Sample—191 plasma disposition curves of amoxicillin obtained from 21 IV, 104 IM, and 66 PO administrations corresponding to 2,098 plasma concentrations.
Procedures—A population model of amoxicillin disposition in pigs was developed for PO and IM administration. The MCS method was then used to determine, for various dosage regimens, the proportion of pigs achieving plasma amoxicillin concentrations greater than a selection of possible minimal inhibitory concentrations (MICs) ranging from 0.0625 to 4 mg/L for at least 40% of a 24-hour period.
Results—A target attainment rate (TAR) of 90% was never achieved with the breakpoint recommended by the Clinical and Laboratory Standards Institute (0.5 mg/L) when the usual recommended dosage (20 mg/kg/d) was used. Only by dividing the orally administered daily dose into 12-hour administration intervals was a TAR > 90% achieved when the total dose was at least 40 mg/kg for a pathogen having an MIC ≤ 0.0625 mg/L. For the IM route, the TAR of 90% could only be achieved for MICs of 0.0625 and 0.125 mg/L with the use of 15 and 30 mg/kg doses, respectively.
Conclusions and Clinical Relevance—Population kinetics and MCS are required to determine robust species-specific interpretive criteria (susceptible, intermediate, and resistant classifications) for antimicrobial susceptibility testing breakpoints (taking into account interanimal variability).
