Procedures—Meloxicam (0.5 mg/kg, IV, or 1.0 mg/kg, PO) was administered in a randomized crossover design with a 10-day washout period. Blood samples were collected at predetermined times over 96 hours. Serum drug concentrations were determined by high-pressure liquid chromatography with mass spectrometry. Computer software was used to estimate values of pharmacokinetic parameters through noncompartmental methods.
Results—Following IV administration (n = 5), the geometric mean (range) elimination half-life was 14.0 hours (10.5 to 17.0 hours), volume of distribution was 0.204 L/kg (0.171 to 0.272 L/kg), and clearance was 0.17 mL/min/kg (0.12 to 0.27 mL/min/kg). Following oral administration (n = 6), maximum serum concentration was 1.72 μg/mL (1.45 to 1.93 μg/mL), time to maximum serum concentration was 19.0 hours (12.0 to 24.0 hours), clearance per bioavailability was 0.22 mL/min/kg (0.16 to 0.30 mL/min/kg), and terminal half-life was 15.4 hours (13.2 to 17.7 hours). Bioavailability of orally administered meloxicam was calculated as 72% (40% to 125%; n = 5). No adverse effects were evident following meloxicam administration via either route.
Conclusions and Clinical Relevance—Meloxicam administered PO at 1.0 mg/kg has good bioavailability with slow elimination kinetics in sheep. These data suggested that meloxicam may be clinically useful, provided the safety and analgesic efficacy of meloxicam as well as feed-related influences on its pharmacokinetics are established in ruminants.
Objective—To determine the pharmacokinetics of meloxicam (1 mg/kg) in rabbits after oral administration of single and multiple doses.
Animals—6 healthy rabbits.
Procedures—A single dose of meloxicam (1 mg/kg, PO) was administered to the rabbits. After a 10-day washout period, meloxicam (1 mg/kg, PO) was administered to rabbits every 24 hours for 5 days. Blood samples were obtained from rabbits at predetermined intervals during both treatment periods. Plasma meloxicam concentrations were determined, and noncompartmental pharmacokinetic analysis was performed.
Results—The mean peak plasma concentration and area under the plasma concentration-versus-time curve extrapolated to infinity after administration of a single dose of meloxicam were 0.83 μg/mL and 10.37 h•μg/mL, respectively. After administration of meloxicam for 5 days, the mean peak plasma concentration was 1.33 μg/mL, and the area under the plasma concentration-versus-time curve from the time of administration of the last dose to 24 hours after that time was 18.79 h•μg/mL. For single- and multiple-dose meloxicam experiments, the mean time to maximum plasma concentration was 6.5 and 5.8 hours and the mean terminal half-life was 6.1 and 6.7 hours, respectively.
Conclusions and Clinical Relevance—Plasma concentrations of meloxicam for rabbits in the present study were proportionally higher than those previously reported for rabbits receiving 0.2 mg of meloxicam/kg and were similar to those determined for animals of other species that received clinically effective doses. A dose of 1 mg/kg may be necessary to achieve clinically effective circulating concentrations of meloxicam in rabbits, although further studies are needed.
To characterize the pharmacokinetics of a single oral dose (6 mg/kg) of mavacoxib in New Zealand White rabbits (Oryctolagus cuniculus) and to characterize any clinicopathologic effects with this medication and dose.
Six healthy, 4-month-old New Zealand White rabbits (3 male, 3 female).
Before drug administration, clinicopathologic samples were collected for baseline data (CBC, serum biochemical analyses, and urinalysis including urine protein-to-creatinine ratio). All 6 rabbits received a single oral dose (6 mg/kg) of mavacoxib. Clinicopathologic samples were collected at set time intervals to compare with the baseline. Plasma mavacoxib concentrations were determined using liquid chromatography with mass spectrometry, and pharmacokinetic analysis was performed using non-compartmental methods.
After a single oral dose, the maximum plasma concentration (Cmax; mean, range) was 854 (713–1040) ng/mL, the time to Cmax (tmax) was 0.36 (0.17–0.50) days, the area under the curve from 0 to the last measured time point (AUC0-last) was 2000 (1765–2307) days*ng/mL, the terminal half-life (t1/2) was 1.63 (1.30–2.26) days, and the terminal rate constant (λz) was 0.42 (0.31–0.53) days. All results for CBCs, serum biochemical analyses, urinalyses, and urine protein-to-creatinine ratios remained within published normal reference intervals.
This study determined that plasma concentrations reached target levels of 400 ng/mL for 48 hours in 3/6 rabbits at 6 mg/kg PO. In the remaining 3/6 rabbits, the plasma concentrations were 343–389 ng/mL at 48 hours, which is below the target concentration. Further research is needed to make a dosing recommendation, including a pharmacodynamic study and investigating pharmacokinetics at different doses and multiple doses.
Objective—To determine the pharmacokinetics of marbofloxacin after oral administration in juvenile harbor seals (Phoca vitulina) at a dose of 5 mg/kg (2.3 mg/lb) and to compare pharmacokinetic variables after pharmacokinetic analysis by naïve averaged, naïve pooled, and nonlinear mixed-effects modeling.
Animals—33 male and 22 female juvenile seals being treated for various conditions.
Procedures—Blood collection was limited to ≤ 3 samples/seal. Plasma marbofloxacin concentrations were measured via high-pressure liquid chromatography with UV detection.
Results—Mean ± SE dose of marbofloxacin administered was 5.3 ± 0.1 mg/kg (2.4 ± 0.05 mg/lb). The terminal half-life, volume of distribution (per bioavailability), and clearance (per bioavailability) were approximately 5 hours, approximately 1.4 L/kg, and approximately 3 mL/min/kg, respectively (values varied slightly with the method of calculation). Maximum plasma concentration and area under the plasma-time concentration curve were approximately 3 μg/mL and 30 h·μg/mL, respectively. Naïve averaged and naïve pooled analysis appeared to yield a better fit to the population, but nonlinear mixed-effects modeling yielded a better fit for individual seals.
Conclusions and Clinical Relevance—Values of pharmacokinetic variables were similar regardless of the analytic method used. Pharmacokinetic variability can be assessed with nonlinear mixed-effects modeling, but not with naïve averaged or naïve pooled analysis. Visual observation by experienced trainers revealed no adverse effects in treated seals. Plasma concentrations attained with a dosage of 5 mg/kg every 24 hours would be expected to be efficacious for treatment of infections caused by susceptible bacteria (excluding Pseudomonas aeruginosa).
Objective—To determine the pharmacokinetics of morphine after IM administration in a clinical population of horses.
Design—Prospective clinical study.
Procedures—Morphine sulfate (0.1 mg/kg [0.045 mg/lb], IM) was administered to horses, and blood samples were obtained at predetermined time points. Plasma morphine concentrations were measured via liquid chromatography and mass spectrometry. In preliminary investigations, samples were obtained from 2 healthy horses at 12 time points (up to 12 hours after drug administration) and analyzed via 2-stage pharmacokinetic analysis. In the clinical phase, blood samples were obtained from 75 hospitalized horses at various times (total, 2 to 3 samples/horse) up to 9 hours after drug administration, and data were analyzed via a naïve pooled pharmacokinetic model.
Results—In the clinical phase, the apparent terminal half-life (t½) of morphine was approximately 1.5 hours, volume of distribution per bioavailability was approximately 4.5 L/kg, and clearance per bioavailability was approximately 35 mL/kg/min. Peak plasma concentration in naïve pooled analysis was 21.6 ng/mL and occurred approximately 4 minutes after administration. Morphine concentrations were below the limit of quantification ≤ 7 hours after administration in 74 horses. Adverse effects attributed to morphine administration were uncommon and considered mild.
Conclusions and Clinical Relevance—The short t½ of morphine in horses suggested frequent administration may be needed to maintain targeted plasma concentrations. Variations in plasma concentrations suggested optimal dosages may differ among horses. The drug was well tolerated at the described dose, but patients receiving morphine should be monitored carefully.
Objective—To assess the use of a von Frey device as
a mechanical nociceptive stimulus for evaluation of
the antinociceptive effects of morphine in dogs and
its potential application in the pharmacodynamic modeling
of morphine in that species.
Animals—6 healthy Beagles.
Procedure—von Frey thresholds were measured in
all dogs before and at intervals after they received no
treatment (control dogs) and IV administration of morphine
sulfate (1 mg/kg; treated dogs) in a crossover
study. The von Frey device consisted of a rigid tip
(0.5 mm in diameter) and an electronic load cell; the
operator was unaware of recorded measurements.
Results—Application of the von Frey device was
simple and well tolerated by all dogs and caused no
apparent tissue damage. No significant changes in
thresholds were detected in the control dogs at 8
hourly measurements, indicating a lack of acquired
tolerance, learned aversion, or local hyperalgesia.
When assessed as a group, treated dogs had significantly
high thresholds for 4 hours following morphine
administration, compared with baseline values;
individually, thresholds decreased to baseline
values within (mean ± SE) 2.8 ± 0.6 hours. The
maximal effect (change from baseline values) was
213 ± 43%, and the plasma morphine concentration
to achieve 50% maximal effect was
13.92 ± 2.39 ng/mL.
Conclusions and Clinical Relevance—Data suggest
that, in dogs, evaluation of the antinociceptive effect
and pharmacodynamic modeling of a dose of morphine
sulfate (1 mg/kg, IV) can be successfully
achieved by use of a von Frey device. (Am J Vet Res
Objective—To evaluate the pharmacokinetics and pharmacodynamics
of morphine after IV administration as
an infusion or multiple doses in dogs by use of a von
Frey (vF) device.
Procedure—In the first 2 crossover experiments of a
3-way crossover study, morphine or saline (0.9%) solution
was administered via IV infusion. Loading doses
and infusion rates were administered to attain targeted
plasma concentrations of 10, 20, 30, and 40 ng/mL.
In the third experiment, morphine (0.5 mg/kg) was
administered IV every 2 hours for 3 doses. The vF
thresholds were measured hourly for 8 hours. Plasma
concentrations of morphine were measured by highpressure
Results—No significant changes in vF thresholds
were observed during infusion of saline solution. The
vF thresholds were significantly increased from 5 to 8
hours during the infusion phase, corresponding to targeted
morphine plasma concentrations > 30 ng/mL
and infusion rates ≥ 0.15 ± 0.02 mg/kg/h. The maximal
effect (EMAX) was 78 ± 11% (percentage change from
baseline), and the effective concentration to attain a
50% maximal response (EC50) was 29.5 ± 5.4 ng/mL.
The vF thresholds were significantly increased from 1
to 7 hours during the multiple-dose phase; the EC50
and EMAX were 23.9 ± 4.7 ng/mL and 173 ± 58%,
respectively. No significant differences in half-life, volume
of distribution, or clearance between the first and
last dose of morphine were detected.
Conclusions and Clinical Relevance—Morphine
administered via IV infusion (0.15 ± 0.02 mg/kg/h) and
multiple doses (0.5 mg/kg, IV, every 2 hours for 3
doses) maintained significant antinociception in dogs.
(Am J Vet Res 2005;66:1968–1974)
OBJECTIVE To assess the pharmacokinetic properties of cefovecin in a cold-water teleost species.
ANIMALS 10 healthy adult copper rockfish (Sebastes caurinus), sex unknown.
PROCEDURES Cefovecin (16 mg/kg) was administered SC to the rockfish. Blood samples were collected at predetermined points for measurement of plasma cefovecin concentrations (3 samples/fish). Plasma cefovecin concentrations were measured via liquid chromatography with mass spectrometry. Pharmacokinetic analysis was performed by means of naïve pooled analysis and compartmental modeling. Plasma protein binding of cefovecin was determined by ultrafiltration.
RESULTS Cefovecin administration appeared to be well tolerated by the rockfish. Pharmacokinetic analysis resulted in a maximum plasma concentration of 104.8 μg/mL at 2.07 hours after administration. Plasma terminal half-life was 32.5 hours, and area under the curve was 5,132 h·g/mL. Plasma protein binding was low (< 10%) for plasma concentrations of 10 and 100 μg of cefovecin/mL when assessed at 7.8° and 20°C. Plasma concentrations > 1 μg/mL persisted for the full 7-day follow-up period.
CONCLUSIONS AND CLINICAL RELEVANCE SC administration of cefovecin to copper rockfish at a dose of 16 mg/kg yielded plasma concentrations > 1 μg/mL that persisted to 7 days, but some interindividual variability was observed. The low degree of plasma protein binding but high circulating concentration of free drug may allow an extended administration interval in rockfish. Studies are needed to assess the efficacy and safety of this dose in rockfish.
PROCEDURES Enrofloxacin (20 mg/kg) was administered SC once to 6 prairie dogs and IV once to 2 prairie dogs. A blood sample was collected from each animal immediately before (0 hours) and 0.5, 1, 2, 4, 8, 12, and 24 hours after drug administration to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin. Plasma enrofloxacin and ciprofloxacin concentrations were quantified with ultraperformance liquid chromatography–mass spectrometry, and noncompartmental pharmacokinetic analysis was performed.
RESULTS Enrofloxacin was biotransformed to ciprofloxacin in the prairie dogs used in the study. For total fluoroquinolones (enrofloxacin and ciprofloxacin), the mean (range) of peak plasma concentration, time to maximum plasma concentration, and terminal half-life after SC administration were 4.90 μg/mL (3.44 to 6.08 μg/mL), 1.59 hours (0.5 to 2.00 hours), and 4.63 hours (4.02 to 5.20 hours), respectively.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that administration of enrofloxacin (20 mg/kg, SC, q 24 h) in black-tailed prairie dogs may be appropriate for treatment of infections with bacteria for which the minimum inhibitory concentration of enrofloxacin is ≤ 0.5 μg/mL. However, clinical studies are needed to determine efficacy of such enrofloxacin treatment.
Objective—To evaluate the bioavailability and pharmacokinetic
characteristics of 2 commercially available
extended-release theophylline formulations in
Design—Randomized 3-way crossover study.
Animals—6 healthy adult dogs.
Procedure—A single dose of aminophylline (11 mg·kg–1
[5 mg·lb–1], IV, equivalent to 8.6 mg of theophylline/kg
[3.9 mg·lb–1]) or extended-release theophylline tablets
(mean dose, 15.5 mg·kg–1 [7.04 mg·lb–1], PO) or capsules
(mean dose, 15.45 mg·kg–1 [7.02 mg·lb–1], PO) was
administered to all dogs. Blood samples were obtained
at various times for 36 hours after dosing; plasma was
separated and immediately frozen. Plasma samples
were analyzed by use of fluorescence polarization
Results—Administration of theophylline IV best fit a
2-compartment model with rapid distribution followed
by slow elimination. Administration of extended-release
theophylline tablets and capsules best fit a 1-
compartment model with an absorption phase. Mean
values for plasma terminal half-life, volume of distribution,
and systemic clearance were 8.4 hours, 0.546
L·kg–1, and 0.780 mL·kg–1·min–1, respectively, after IV
administration of theophylline. Systemic availability
was > 80% for both oral formulations. Computer simulations
predicted that extended-release theophylline
tablets or capsules administered at a dosage of 10
mg·kg–1 (4.5 mg·lb–1), PO, every 12 hours would maintain
plasma concentrations within the desired therapeutic
range of 10 to 20 µg·mL–1.
Conclusions and Clinical Relevance—Results of
these single-dose studies indicated that administration
of the specific brand of extended-release theophylline
tablets or capsules used in this study at a
dosage of 10 mg·kg–1, PO, every 12 hours would
maintain plasma concentrations within the desired
therapeutic range (10 to 20 µg·mL–1) in healthy dogs.
(J Am Vet Med Assoc 2004;224:1113–1119)