Pharmacokinetics after subcutaneous administration of a single dose of cefovecin sodium in African lions (Panthera leo)

Kelly P. Flaminio Oregon Zoo, 4001 SW Canyon Rd, Portland, OR 97221.

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John Mark Christensen Department of Pharmaceutical Science, College of Pharmacy, Oregon State University, Corvallis, OR 97331.

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Sultan Mohammed Alshahrani Department of Pharmaceutical Science, College of Pharmacy, Oregon State University, Corvallis, OR 97331.

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Sumeia Mohammed Mohammed Department of Pharmaceutical Science, College of Pharmacy, Oregon State University, Corvallis, OR 97331.

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Abstract

OBJECTIVE To determine the pharmacokinetics of cefovecin sodium after SC administration of a single dose to African lions (Panthera leo).

ANIMALS 3 adult (9 to 10 years old; 1 male and 2 females) and 3 juvenile (2 years old; 1 male and 2 females) African lions.

PROCEDURES A crossover study was conducted. A single dose of cefovecin was administered SC at 4 mg/kg (half dose) and 8 mg/kg (full dose) to African lions. Blood samples were collected daily for 14 days after cefovecin injection. Plasma drug concentrations were determined by use of high-performance liquid chromatography with UV detection.

RESULTS Cefovecin had first-order elimination kinetics for doses of 4 and 8 mg/kg. Mean ± SD maximum plasma concentration was 9.73 ± 1.01 μg/mL and 18.35 ± 0.94 μg/mL after doses of 4 and 8 mg/kg, respectively. Time to maximum plasma concentration was approximately 4 hours for both doses. Mean elimination half-life was approximately 111 and 115 hours after doses of 4 and 8 mg/kg, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE Cefovecin was detected in lion plasma for 336 hours after administration at both 4 and 8 mg/kg at concentrations greater than the reported minimum inhibitory concentration (0.06 μg/mL) for common bacterial organisms in domestic cats. These results indicated that cefovecin administered at 4 mg/kg SC reached therapeutic concentrations for an extended period in African lions.

Abstract

OBJECTIVE To determine the pharmacokinetics of cefovecin sodium after SC administration of a single dose to African lions (Panthera leo).

ANIMALS 3 adult (9 to 10 years old; 1 male and 2 females) and 3 juvenile (2 years old; 1 male and 2 females) African lions.

PROCEDURES A crossover study was conducted. A single dose of cefovecin was administered SC at 4 mg/kg (half dose) and 8 mg/kg (full dose) to African lions. Blood samples were collected daily for 14 days after cefovecin injection. Plasma drug concentrations were determined by use of high-performance liquid chromatography with UV detection.

RESULTS Cefovecin had first-order elimination kinetics for doses of 4 and 8 mg/kg. Mean ± SD maximum plasma concentration was 9.73 ± 1.01 μg/mL and 18.35 ± 0.94 μg/mL after doses of 4 and 8 mg/kg, respectively. Time to maximum plasma concentration was approximately 4 hours for both doses. Mean elimination half-life was approximately 111 and 115 hours after doses of 4 and 8 mg/kg, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE Cefovecin was detected in lion plasma for 336 hours after administration at both 4 and 8 mg/kg at concentrations greater than the reported minimum inhibitory concentration (0.06 μg/mL) for common bacterial organisms in domestic cats. These results indicated that cefovecin administered at 4 mg/kg SC reached therapeutic concentrations for an extended period in African lions.

Cefovecin sodium is a third-generation cephalosporin developed as a single-dose, long-acting antimicrobial for use in dogs and cats.1 The pharmacokinetic profile of cefovecin is unique because of its long half-life (up to 5 days and up to 7 days in dogs and cats, respectively), extremely high protein binding, and high bioavailability after SC administration.2–5 These properties make cefovecin effective against bacterial infections for an extended period (up to 14 days) after a single SC injection in some species.1,6–8 Cefovecin is approved for the treatment of skin infections caused by gram-positive and gram-negative bacteria (Staphylococcus intermedius, Staphylococcus canis, and Pasteurella multocida) in dogs and cats and also has efficacy for treating urinary tract infections caused by Escherichia coli in cats.1,8 Because of its pharmacological properties in domestic animals (long t1/2 and broad spectrum of antimicrobial action), cefovecin is a highly desirable antimicrobial for use in exotic species, which commonly leads to empirical extralabel use.a

African lions (Panthera leo) are the most well-represented felids identified by the Taxon Advisory Group in North American zoos accredited by the Association of Zoos and Aquariums. The African lion Species Survival Plan program currently encompasses the largest population of animals and also involves the highest number of institutions belonging to the Association of Zoos and Aquariums of all the felid Species Survival Plan programs.9 The Panthera genus also includes tigers (Panthera tigris), leopards, snow leopards, and jaguars. Currently, no antimicrobial drugs are approved by the FDA for the treatment of nondomestic felids, although extralabel use of antimicrobials is commonly practiced by zoo veterinarians despite evidence that some drugs have differences in therapeutic effects in different species.a Therefore, it is important to obtain pharmacokinetic information for antimicrobials to enable clinicians to better select appropriate dosages and routes of administration for nondomestic animals, rather than relying on extrapolation of data from other species.

African lions typically are housed in family groups in zoos and may require antimicrobial treatment for a variety of conditions. Broad-spectrum antimicrobials (eg, cefovecin) that penetrate most tissue and fluid compartments are common choices for many of these conditions. Anecdotal use of cefovecin has been reported in domestic and exotic felids for the successful treatment of dental abscesses, periodontal disease, diarrhea, and systemic bacteremia, and it is commonly administered after laparotomy to prevent secondary infections.10–12 This has prompted multiple investigations to determine the pharmacokinetics of cefovecin in a variety of nondomestic species, including tigers.2,3,6,7,13–15 Differences in the mean plasma t1/2 of cefovecin reported in these animals imply that pharmacokinetic studies are needed for each species to determine accurate dosing regimens.

In zoo and wildlife medicine, cefovecin has the potential to be useful for animals that are not compliant with or will not tolerate orally administered medications.a Pharmacokinetic evaluation of cefovecin in African lions is essential for the prevention and effective treatment of susceptible bacterial disease as well as to minimize antimicrobial resistance secondary to treatments resulting in inadequate therapeutic plasma concentrations. Evaluation is also important for assessing safety and possible adverse effects. Therefore, the objective of the study reported here was to define pharmacokinetics of cefovecin in African lions after SC administration at 2 doses. A secondary objective was to develop a recommendation regarding the dosage of cefovecin for this species.

Materials and Methods

Animals

Six African lions (3 adults [1 male, 10 years old; 2 females, 9 years old] and 3 juveniles [1 male and 2 females, 2 years old]) housed at the Oregon Zoo were included in the study. Sample size was determined on the basis of the number of lions trained to accept injections and allow phlebotomies. Body weight of the 3 adult lions ranged from 116 to 246 kg, and body weight of the 3 juvenile lions ranged from 129 to 184 kg. Before they were included in the study, all lions were visually examined and hematologically evaluated (a CBC and biochemical panel). Diagnostic test results were within reference limits, and all lions were deemed healthy and at ideal body condition.b The lions had access to the exhibit and holding area, and their diet was strictly managed to ensure body condition remained stable throughout the study. To minimize stress, all lions were trained to allow blood collection from both lateral coccygeal veins and the right lateral saphenous vein by use of a static chute with removable training windows. During the study, injection and phlebotomy sites as well as general health of the lions were monitored by the zoo keeper and veterinary staff. The study was approved by the Oregon Zoo Animal Welfare Committee in accordance with the Association of Zoos and Aquariums standards for research and technology.

Experimental procedures

A crossover study was conducted. Vials of cefovecin sodiumc were reconstituted with the provided diluent (sterile water) to create a final concentration of 250 mg/mL.16 Animals were weighed within 1 week before drug administration. Cefovecin was administered SC at a dose of 4 or 8 mg/kg. There was a minimum 60-day washout period between the 4- and 8-mg/kg doses administered to each animal. All injections were administered by use of a 1-inch, 20-gauge needle at a single location in the right lateral aspect of the thigh. After the needle was inserted, aspiration was used to ensure the drug was not injected IV. Blood samples (3 to 5 mL/sample) were collected by use of a 1-inch, 22-gauge needle and 6-mL syringe. One blood sample was collected 12 to 24 hours before drug administration, and additional blood samples were collected 2, 4, 8, 24, 72, 96, 144, 192, 240, 288, and 336 hours after administration. Collection of blood samples was rotated among the 3 available venipuncture sites (right lateral coccygeal vein, left lateral coccygeal vein, and right saphenous vein). If a hematoma formed, that phlebotomy site was not used until the swelling resolved. Each site was cleaned with 96% ethanol prior to venipuncture. Blood samples were immediately placed in 10-mL tubes containing sodium heparin and centrifugedd at 1,163 × g for 5 minutes. Plasma was transferred to nonreactive tubes and stored at −80°C until shipped to Oregon State University for analysis.

Sample preparation

All reagents and solvents used in the study were HPLC grade; they included deionized purified water, methanol, acetonitrile,d and acetic acid.e Chromatographic analysis was conducted with an HPLC system.f Plasma samples were centrifugedg and filtered by use of 0.22-μm nylon filterse before they were injected into the HPLC column.

Method validation and analysis

An HPLC method for quantification of cefovecin in lion plasma was developed and validated by use of a C18 column (4.6 × 150 mm; 5 μm)f connected to another columnh and a sample flow-through inline filter.i The mobile phase consisted of a solution of acetonitrile:water:methanol (60:20:20; pH, 3.1 as adjusted by use of acetic acid) at a flow rate of 0.7 mL/min. The UV detector wavelengths were set at 254 and 290 nm, and column temperature was set at 25°C. Sample injection volume was 15 μL with a run time of 10 minutes.

Calibration curves were created, and quality control analyses of samples were performed. Lion plasma was spiked with cefovecin stock solution (250 mg/mL) to create concentrations for the calibration curve (range, 0.1 to 100 μg/mL). Samples were prepared by pipetting 0.5 mL of plasma into a 2-mL Eppendorf centrifuge tube. Then, 0.5 mL of plasma for all lion samples, 0.5 mL of standard curve samples, and 0.5 mL of the quality control samples were each combined with an equal 0.5-mL volume of a mixture of glacial acetic acid and methanol (50 μL of glacial acetic acid was added to 0.45 mL of methanol). Contents of tubes were mixed on a vortex device for 1 minute, allowed to denature for 15 minutes, and then centrifuged at 1,100 × g for 25 minutes. Supernatant was filtered through a 0.22-μm filter and injected into the HPLC column.

Pharmacokinetic parameters for cefovecin were estimated by use of commercial software.j A noncompartmental model-independent method was used to analyze the plasma concentration-time curve and ke obtained by regression of the terminal part of the plasma concentration-time curve. The value for t1/2 was estimated by use of the equation ln2/ke, where ln2 (natural logarithm of 2) is 0.693. Statistical analysisk was performed by use of an ANOVA and paired t tests to compare pharmacokinetic parameters obtained after injection of 4 and 8 mg/kg. Values were considered significant at P < 0.05.

The limit of detection was 50 ng/mL, and the limit of quantification was 100 ng/mL. Assay precision for variability was calculated; mean coefficient of variation was 5.4% (range, 2.4% for the highest [100 μg/mL] plasma concentration to 7.2% for the lowest [0.1 ng/mL] plasma concentration). Recovery of cefovecin ranged from 89% to 92.25% (mean ± SD, 89.8 ± 2.02%). Recovery measurements were performed 5 times during the study to ensure recovery of cefovecin remained consistent throughout the study.

Evaluation of plasma protein binding

Lion plasma was obtained before the administration of cefovecin to investigate in vitro protein binding of cefovecin to lion plasma proteins. The RED method used to assess protein binding by use of an equilibrium dialysis membrane device (low-molecular-weight semipermeable membrane with a pore size of 0.22 μm to separate dialysis chambers and prevent plasma proteins from crossing the membrane). Three samples of plasma were prepared at 3 cefovecin concentrations (7.5, 12.0, and 18.5 μg/mL). An aliquot (1,000 μL) of plasma spiked with cefovecin and a phosphate buffer solution (pH, 7.2) were injected into the RED device on separate sides of the membrane. The RED device was then incubated at 37°C for 24 hours to allow equilibrium for drug-plasma protein binding. After equilibrium was achieved, 0.5-mL samples were collected from both RED chambers; samples were diluted with an equal volume of solution from the other chamber (as appropriate) and centrifuged at 1,110 × g for 20 minutes, which was followed by analysis with HPLC for determination of cefovecin concentrations. At equilibrium (ie, final drug concentration in the plasma side and buffer side remained constant), protein binding was expressed as a percentage of the cefovecin concentration by calculation of the percentage of plasma protein binding as follows: percentage bound = ([total concentration – unbound concentration]/total concentration) × 100.

Results

No adverse effects were observed in any of the 6 lions after SC administration of cefovecin at a dose of 4 or 8 mg/kg. Additionally, no adverse effects were seen as a result of repeated collection of blood samples, except that there were 6 hematomas of 142 phlebotomies (4.2%). Each of the hematomas was mild and resolved within 24 hours after development.

Mean concentration-time curves after SC administration of a single dose of cefovecin at 4 and 8 mg/kg were plotted (Figure 1). Pharmacokinetic parameters for cefovecin after SC administration of cefovecin at 4 and 8 mg/kg were calculated (Table 1). The AUC and Cmax of cefovecin for the 8-mg/kg dose were approximately twice the values for the 4-mg/kg dose, which indicated linear pharmacokinetics. All lions had measurable plasma concentrations of cefovecin 336 hours after administration; mean concentration at 336 hours was 0.89 and 1.22 μg/mL for the 4- and 8-mg/kg doses, respectively. Cefovecin was not detected in any of the plasma samples before administration of the second cefovecin dose, which indicated a 60-day washout period was sufficient.

Figure 1—
Figure 1—

Mean ± SD plasma concentration of cefovecin in 6 African lions (Panthera leo) after SC administration of a single dose at 4 mg/kg (A) and 8 mg/kg (B).

Citation: American Journal of Veterinary Research 80, 3; 10.2460/ajvr.80.3.230

Table 1—

Mean ± SD values for pharmacokinetic parameters of cefovecin sodium in 6 African lions (Panthera leo) after SC administration of a single dose at 4 and 8 mg/kg.

Parameter4 mg/kg8 mg/kg
t1/2 (h)*111.4 ± 73.1115.1 ± 35.7
ke (h−1)0.006 ± 0.0030.006 ± 0.002
Tmax (h)4.33 ± 1.974.00 ± 0
Cmax (μg/mL)9.73 ± 1.0118.35 ± 0.94
AUC (μg/mL/h)1,343.7 ± 1,257.21,855.5 ± 276.3
MRT (h)261.8 ± 303.6153.5 ± 49.9

Value reported is harmonic mean ± SD.

MRT = Mean residence time. Tmax = Time to reach Cmax.

Mean protein binding for cefovecin in the 3 concentrations tested (7.5, 12.0, and 18.5 μg/mL) was approximately 99% (range, 98.4% to 99.15%).

Discussion

Cefovecin is commonly administered to domestic dogs and cats because of its broad spectrum and long t1/2; however, there is limited information about cefovecin's pharmacokinetic effectiveness in exotic felids. To our knowledge, the study reported here was the first in which the pharmacokinetics and safety of cefovecin in African lions have been evaluated. A wide range of doses and administration routes has been evaluated in a variety of species; however, the most common dose and route was 8 mg/kg, SC, which was in agreement with the recommended published dose for domestic species as well as with previously reported empirical use in exotic felids.2,3,6,7,10–14 Dilution of cefovecin to a final concentration of 250 mg/mL (rather than the manufactured concentration of 80 mg/mL) yielded good results and caused no adverse effects at the injection sites or signs of pain during injection.7 Because of the relatively high body weight of African lions, this higher-concentration solution allowed for a smaller injection volume, which increased ease of administration of the drug.

Findings of the present study indicated that cefovecin had linear pharmacokinetics for the dose range of 4 to 8 mg/kg, which resulted in a doubling of Cmax. The AUC of cefovecin for the dose of 8 mg/kg was almost double the AUC for the dose of 4 mg/kg, as expected.

The mean ± SD t1/2 of cefovecin was similar after SC administration of 4 and 8 mg/kg (111.4 ± 73.1 hours and 115.1 ± 35.7 hours, respectively). This result is similar to the t1/2 for domestic dogs and cats (133 and 170 hours, respectively) but longer than the t1/2 for other nondomestic species (< 24 hours), except for tigers (227.8 hours) and Patagonia sea lions (11.3 to 21.6 days).2–7,13,14 The Cmax of cefovecin was substantially lower for African lions (9.73 and 18.35 μg/mL after administration of 4 and 8 mg/kg, respectively), compared with the value for tigers (214.2 μg/mL), domestic cats (141 to 216 μg/mL), and dogs (121 μg/mL). However, cefovecin reached the Cmax more quickly in African lions (4 hours) than in dogs (6.2 hours) and tigers (22.3 hours) but more slowly than in domestic cats (1 to 2 hours).4,5,14 These data indicated that the Cmax of cefovecin in African lions was higher than the minimum effective concentration extrapolated from other species for both doses. The data also indicated that cefovecin reached concentrations that would be therapeutic against bacterial organisms by 4 hours after SC administration.

As mentioned previously, pharmacokinetic parameters differ when values for African lions are compared with values for tigers, despite the fact both species belong to the Panthera genus. This could possibly be related to route of administration (IM in tigers and SC in lions), use of anesthesia to obtain plasma samples in tigers, or species-specific differences in metabolism of cefovecin. Differences in pharmacokinetic parameters between these 2 related species have also been reported for the NSAID meloxicam.l Therefore, pharmacokinetic studies ideally should be performed for each species despite phylogenetic relationships.

The AUC in African lions was the same or greater than results reported in most other species, which was likely the result of lower cefovecin clearance in lions because of high protein binding and a greater volume of distribution.2–7,13,14 The higher AUC and lower clearance (longer t1/2) implied that a lower recommended dose (4 mg/kg) of cefovecin could be used to treat microbial infections in lions. This conclusion is supported by pharmacodynamic studies4,5 of cefovecin in which it was determined that the growth of common pathogens of domestic dogs and cats was inhibited when plasma drug concentrations remain above the MIC90 (> 0.25 μg/mL for 7 days after treatment and 0.06 μg/mL for 14 days after treatment). Reports10–12,16 of bacterial infections in large felids indicated profiles that were susceptible to cefovecin, which therefore supports the potential effectiveness of cefovecin against these pathogens in exotic cats.

The SC administration of cefovecin to African lions appeared to be safe and resulted in effective plasma concentrations with a pharmacokinetic profile more similar to those of domestic dogs and cats than to those of other exotic species. Cefovecin had a long half-life after SC administration in African lions and had linear pharmacokinetics when the dose was doubled. On the basis of the MIC90 (range, 0.06 to 0.25 μg/mL) for cefovecin against common microorganisms, it is expected that SC administration of a 4-mg/kg dose of cefovecin (concentration, 250 mg/mL) every 14 days would achieve adequate serum concentrations for efficacy. However, because cefovecin had linear pharmacokinetics, increasing the dose to 8 mg/kg could still be safe and effective if the MIC90 for an organism were > 0.25 μg/mL. Therefore, we believe cefovecin can be used to provide safe, long-lasting antimicrobial treatment for lions that cannot easily be medicated or cannot tolerate orally administered antimicrobials. However, bacterial culture and susceptibility testing should ideally be performed prior to treatment with cefovecin to ensure the causative organism is susceptible to cefovecin and to prevent the development of antimicrobial-resistant bacteria.

Acknowledgments

The authors declare there were no financial conflicts of interest.

The authors thank Beth Foster and Laura Weiner for assistance in training the lions to accept injections and allow collection of blood samples.

ABBREVIATIONS

AUC

Area under the plasma concentration–time curve

Cmax

Maximum drug concentration

HPLC

High-performance liquid chromatography

ke

Elimination rate constant

MIC90

Minimum inhibitory concentration at which 90% of isolates are inhibited

RED

Rapid equilibrium dialysis

t1/2

Elimination half-life

Footnotes

a.

Bertelsen MF, Thuesen LR, Bakker J, et al. Limitations and usages of cefovecin in zoological medicine (abstr), in Proceedings. Int Conf Dis Zoo Wild Anim 2010;140–141.

b.

Global reference intervals, ZIMS, Species360, Minneapolis, Minn.

c.

Convenia, Zoetis, Kalamazoo, Mich.

d.

Clay Adams compact II, Fisher Scientific, Fair Lawn, NJ.

e.

VWR International, Radnor, Pa.

f.

Kinetex, Phenomenex, Torrance, Calif.

g.

Eppendorf 5415C, Brinkmann Instruments, Westbury, NY.

h.

Security guard 2.1–4.6, VWR International, Radnor, Pa.

i.

KrudKatcher ultra HPLC, Phenomenex, Torrance, Calif.

j.

WinNonLin, version 5.2, Pharsight Corp, Sunnyvale, Calif.

k.

R, version 3.3.3, R Foundation for Statistical Computing, Vienna, Austria.

l.

Visser M, Bronson E, Boothe D. Preliminary population pharmacokinetics of meloxicam in lion (Panthera leo), cheetah (Acinonyx jubatus), and tiger (Panthera tigris) (abstr), in Proceedings. Am Assoc Zoo Vet Annu Conf 2017;89–90.

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