Populations of African cheetahs (Acinonyx jubatus) in North American zoos have increased greatly since the 1990s, with up to 400 individuals in breeding programs for conservation efforts.1 Although cheetahs can be trained for diagnostics, such as venipuncture and radiographs, anesthesia for improved handling during illness or preventative health examinations is often necessary.2 Immobilization and handling techniques that both maximize welfare and minimize oxidative stress biomarkers in captured cheetahs should be considered.2,3 To date, no studies have evaluated the efficacy of oral sedation in cheetahs.
Gabapentin as an anxiolytic that is frequently prescribed.4–11 In addition to anxiolytic properties, gabapentin is widely used as an antiepileptic and analgesic.5,8,12,13 As its name implies, gabapentin has a similar structure to GABA but does not interact with GABA receptors or GABA reuptake or act as a GABA agonist.12,14 Gabapentin is suspected to inhibit excitatory neurotransmitter release by binding and blocking the effect of the α-2-δ subunit of voltage-dependent calcium channels, clinically resulting in antinociception, antiepileptic properties, and decreased anxiety.12,14
When gabapentin was administered to domestic felids prior to stressful events, cat stress were improved, global sedation scores were increased at higher dosages, and for multiple hours postadministration, lower respiratory rates were observed.6,7,9–11 Pharmacokinetic (PK) studies in domestic cats are limited but showed a time to maximum concentration of 1 hour and a maximum plasma concentration (Cmax) of 12.4 μg/mL, with minimal adverse events after administration of between 10 and 20 mg/kg.15,16 Overall, gabapentin appears to be an efficacious and safe option for minimizing stress in cats, which has allowed for extrapolations in zoological medicine.
Gabapentin has been frequently utilized in nondomestic felid medicine; however, no studies have examined pharmacodynamic or PK properties in these species.17–19 Improved understanding of the sedative effects and PK allows for improved handling and minimized stress associated with immobilization in cheetahs. Further understanding the PK parameters of gabapentin in cheetahs will also aid in appropriate dosing and timing to reach target plasma concentrations for antiepileptic and analgesic use in addition to the anxiolytic potential.
The objectives of this study were to assess sedative effects and evaluate the PK of a single administration of oral gabapentin in African cheetahs at 2 dosages. We hypothesized that cheetahs administered an oral gabapentin dosage of 20 mg/kg would experience higher sedation scores when compared to a 10-mg/kg dosage and that the PK profile would be similar to domestic felids.
Methods
Animal use
Study protocols were approved by the IACUC or its equivalent from all participating institutions and received ethical endorsement by the University of California-Davis IACUC (#22650). The study was also endorsed by the Cheetah Species Survival Plan.
A total of 16 cheetahs (7 males and 9 females) were utilized for this study from 3 North American zoological institutions, with an average weight of 42.6 ± 3.3 kg. All cheetahs were primarily housed outdoors with heated shelter and fed in accordance with the Association of Zoos and Aquariums accreditation standards. Inclusion criteria consisted of cheetahs greater than 1 year of age that had undergone a complete blood count and biochemistry blood panel within 1 year with no evidence of liver or renal value elevations, deemed healthy by an attending veterinarian by medical record review and visual examination, trained for venipuncture under behavioral restraint, and not receiving any medications (except for preventative parasiticides). Lactating or pregnant animals were excluded.
Drug administration and sample acquisition
Prior to drug administration, blood was obtained from 5 individuals and combined to form 10 mL of a composite plasma sample, which was used for generation of the calibration curve and to serve as a quality control sample for liquid chromatography tandem mass spectrometry (LC-MS-MS) analysis of plasma samples.
This study was conducted during early spring and summer months in a single-group, sequential design whereby each cheetah received a single dose of gabapentin at 2 dosages separated with a washout period. For the first phase of the study, gabapentin was orally administered at 400 to 500 mg per cheetah with an aim of 10 mg/kg rounded to the nearest 100 due to available capsule sizes (Abbreviated New Drug Application number 204989; ScieGen Pharmaceutical Inc). Gabapentin capsules were placed in a preferred diet item to facilitate ingestion following a 12-hour fast period. Behavioral restraint for venipuncture was conducted from the lateral coccygeal vein to acquire 1.5 to 3 mL of whole blood into heparin collection tubes at the following time points postadministration: 0.5 hours, 1 hour, 1.5 hours, 2 hours, 6 hours, 8 hours, 12 hours, and 24 hours. Due to projected difficulties in patient compliance for repeated sampling, a sparse sampling design was utilized, allowing for collection of at least 3 samples (from 3 different animals) at each time point. Samples were centrifuged for 15 minutes at 1,000 to 2,000 X g, and the resulting supernatant plasma was collected and stored at −80 °C within 1 hour of sample acquisition until shipment of all samples. Samples were shipped next-day delivery on dry ice to an analytical lab for quantification of drug concentrations.
Administration and sample acquisition were repeated after 2 to 3 months at a dose of 800 to 900 mg of gabapentin per cheetah, aiming for 20 mg/kg rounded to the nearest 100. Extra-label drug use in this study population was performed in compliance with the Animal Medicinal Drug Use Clarification Act.
Sedation assessments and monitoring
A subset of 9 cheetahs (5 males and 4 females) from the research population were evaluated for sedation scores via 3 masked scorers who evaluated videos obtained of study animals. Not all cheetahs underwent sedation scoring due to logistical challenges encountered at 1 institution. Scorers were veterinarians experienced with cheetah behavior, and the same 3 masked scorers reviewed each video to reduce the effect of potential inter-rater score variability. Videos were obtained at the same time points that were utilized for PK analysis, including baseline videos prior to medication administration at time point zero, but were performed prior to venipuncture to minimize stimulatory events that may affect behavior or sedation. Videos were randomized for both time point and dose prior to evaluation by the scorers. Scores (0 to 6) were assigned to each video to categorize the level of sedation utilizing a modified feline sedation scoring system (Table 1).10,20
Modified feline sedation scale adapted for use in African cheetahs (Acinonyx jubatus).
| Score | Observation |
|---|---|
| Posture | |
| 0 | Sitting up or walking around with no ataxia |
| 1 | Recumbency with head up or mild ataxia when walking |
| 2 | Recumbency with head down or severe ataxia if walking |
| 3 | Recumbent even if stimulated by noise or movement |
| Behavior | |
| 0 | Alert, normal interactions with conspecifics or husbandry staff |
| 1 | Alert but slower responses to environmental stimuli |
| 2 | Minimal responses |
| 3 | No responses |
| Total | Sedation classification |
| 0 | No sedation |
| 1–2 | Mild sedation |
| 3–4 | Moderate sedation |
| 5–6 | Profound sedation |
Adverse event monitoring occurred during every phase of the study. Any adverse events related to drug administration and repeated phlebotomy, including but not limited to excessive sedation, hypersalivation, dysphoria, prolonged muscle fasciculations, or any signs of hypersensitivity reactions (hives, pruritis, anaphylaxis), were documented.
Gabapentin plasma analysis
Plasma calibrators were prepared by dilution of the gabapentin working standard solutions (Cerilliant) with drug-free cheetah plasma to concentrations ranging from 0.5 to 50,000 ng/mL. As a check of accuracy, quality control samples (drug-free serum fortified with analyte at 2 concentrations within the standard curve) were included. Calibration curves and quality control samples were prepared fresh for each quantitative assay.
Prior to analysis, 200 µL of serum was diluted with 200 µL of acetonitrile (ACN):1 M acetic acid (9:1, v:v) containing 0.1 ng/µL of the internal standard, piroxicam (Sigma Aldrich) to precipitate proteins. The samples were subsequently vortexed for 2 minutes to mix, refrigerated for 20 minutes, vortexed for an additional 1 minute, and centrifuged (4,300 rpm/3,102 X g) for 10 minutes at 4 °C with 20 µL injected into the LC-MS-MS system.
The concentration of gabapentin was measured in serum by LC-MS-MS using positive heated electrospray ionization. Quantitative analysis was performed on a TSQ Altis triple quadrupole mass spectrometer coupled with a Vanquish liquid chromatography system (Thermo Scientific). Chromatography employed an ACE 3 C18 10 cm X 2.1-mm column (Mac-Mod Analytical) and a linear gradient of ACN in water with a constant 0.2% formic acid at a flow rate of 0.35 mL/min. The initial ACN concentration was held at 1% for 0.2 minutes, ramped to 95% over 5.4 minutes, and held at that concentration for 0.1 minutes before re-equilibrating for 4.0 minutes at initial conditions.
Detection and quantification were conducted using selective reaction monitoring of initial precursor ion for gabapentin (m/z, 172.1) and the internal standard piroxicam (m/z, 332.0). The response for the product ions for gabapentin (m/z, 95.1, 137.1) and the internal standard (m/z, 78.3, 95.2) were plotted and peaks at the proper retention time integrated using Quanbrowser software (Thermo Scientific). Quanbrowser software was used to generate calibration curves and quantitate analytes in all samples by linear regression analysis. A weighting factor of 1/X was used for all calibration curves.
Pharmacokinetic analysis
Pharmacokinetic parameters for gabapentin were calculated by noncompartmental analysis of sparse data using commercially available software (Phoenix WinNonlin; Certara). The Cmax values were determined. A full PK evaluation could not be performed due to a lack of terminal time points.
Statistical analysis
Sedation scores were summarized for each dose and time point as mean, SD, median, and range. Differences in mean sedations scores between doses over time were evaluated using a linear mixed effect model in which sedation score was modeled as a function of the time point, dose, and the interaction between time and dose. A random effect was included for each cheetah to account for within-animal correlation. At each time point, the difference between doses was specifically tested using linear contrasts with P values adjusted for multiple testing across all contrasts using the Tukey procedure. We subsequently refit the model without the interaction term because no significant differences were found between doses at any time point. An intraclass correlation was utilized to evaluate for inter-rater reliability. Confidence intervals were generated using 1,000 cluster bootstrap samples with cheetah as the cluster to account for repeated observations within cheetah.
Results
Adverse events
Mild, transient ptyalism was noted between 1 and 8 hours postadministration (n = 3; 17.6%). Mild venipuncture site sensitivities, hematomas, or swellings were also noted (n = 12; 70%), related to venipuncture and not a result of gabapentin administration. Ataxia and sedation were not considered adverse events for this study as occurrences were expected and captured in sedation scoring. Complete resolution of ptyalism and venipuncture site reactions were self-limiting and resolved by 12 hours postadministration and 24 hours post final venipuncture, respectively. Oral administration was well tolerated, and all cats freely consumed the capsules when given with a diet item.
Concentration determination and PK
The assay response was linear and gave correlation coefficients of 0.99 or better. The precision and accuracy of the assay was determined by assaying quality control samples in replicates (n = 6). Accuracy was reported as the percentage of nominal concentration, and precision was reported as the percentage of relative SD. For gabapentin, accuracy was 94% for 6 ng/mL and 93% for 10,000 ng/mL. Precision was 4% for 6 ng/mL and 10% for 10,000 ng/mL. The technique was optimized to provide a limit of quantitation of 0.5 ng/mL and a limit of detection of approximately 0.25 ng/mL for gabapentin.
Mean ± SD maximal plasma concentrations were 24.0 ± 12.8 μg/mL and 31.4 ± 8.57 μg/mL for the 10- and 20-mg/kg doses, respectively (Figure 1). The time to maximum concentration was 12 hours postadministration for both doses. Concentrations were highly variable between animals. For both doses, concentrations remained elevated at 24 hours postadministration, which was the last time point collected (2.39 ± 1.97 and 3.93 ± 3.09 μg/mL for 10 and 20 mg/kg, respectively). Due to the scarcity of samples characterizing the terminal portion of the plasma concentration time curve, a terminal half-life (t1/2) or area under the curve was not calculated.
Mean ± SD gabapentin plasma concentrations over time following oral administration of a single dose in African cheetahs (Acinonyx jubatus). The solid line represents the line of best fit for the data. A—A dosage of 10 mg/kg. B—A dosage of 20 mg/kg. Gabapentin plasma concentrations remained elevated at 24 hours postadministration.
Citation: American Journal of Veterinary Research 85, 12; 10.2460/ajvr.24.07.0200
Sedation scores
Mean sedation scores remained within the mild sedation category for all time points and reached peak scores between 4 and 12 hours postadministration (Figure 2). Inter-rater reliability as measured by intraclass correlation was 0.519 (0.428, 0.605), indicating moderate (0.5 to 0.75) to poor (< 0.5) agreement. Mean sedation scores were not found to differ significantly between the 2 doses at any time point (Table 2). Considering only main effects of dose and time, sedation scores differed significantly over time (P = .001) but not between dosages (P = .260). Sedation scores steadily increased and were significantly higher than baseline at 1.5 hours postadministration and remained elevated through 12 hours (Table 3). All animals had complete resolution of sedation post study completion.
Mean ± SD sedation scores over time for African cheetahs (A jubatus) administered single oral doses of gabapentin at 10 to 20 mg/kg. A modified feline sedation score was utilized for level of sedation, categorization by masked observers with values ranging from zero (no sedation) to 6 (heavy sedation).
Citation: American Journal of Veterinary Research 85, 12; 10.2460/ajvr.24.07.0200
Comparison of mean sedation scores between gabapentin dosages (dosage 1 = 10 mg/kg; dosage 2 = 20 mg/kg) at each time point postadministration in African cheetahs (A jubatus) based on a linear mixed effect model of sedation scores versus time, dosage, and time*dosage interaction.
| Time | Estimate | SE | P value |
|---|---|---|---|
| 0 | 0.073 | 0.463 | .875 |
| 0.5 | −0.871 | 0.594 | .146 |
| 1 | −0.118 | 0.477 | .805 |
| 1.5 | −0.454 | 0.594 | .446 |
| 2 | 0.179 | 0.463 | .701 |
| 4 | −0.111 | 0.748 | .882 |
| 6 | −0.126 | 0.447 | .778 |
| 8 | −0.100 | 0.515 | .847 |
| 12 | −0.778 | 0.748 | .301 |
| 24 | −0.216 | 0.493 | .663 |
Estimate represents the difference between mean sedation scores. P values are adjusted for multiple comparisons using the Tukey procedure.
Coefficient CI from a linear mixed effect model relating sedation scores to time point post gabapentin administration and dose of gabapentin (dose 1 = 10 mg/kg; dose 2 = 20 mg/kg) in African cheetahs (A jubatus).
| Variable (h) | Mean sedation score | SE | P value | Lower CI | Upper CI |
|---|---|---|---|---|---|
| Intercept (0 h, dose 1) | 1.15 | 0.345 | .001 | 0.496 | 1.799 |
| 0.5 | 0.215 | 0.361 | .552 | −0.466 | 0.898 |
| 1 | 0.368 | 0.32 | .254 | −0.239 | 0.972 |
| 1.5 | 0.715 | 0.361 | .05 | 0.034 | 1.398 |
| 2 | 0.583 | 0.315 | .067 | −0.012 | 1.179 |
| 4 | 0.975 | 0.431 | .026 | 0.16 | 1.786 |
| 6 | 1.196 | 0.311 | 0 | 0.61 | 1.784 |
| 8 | 1.12 | 0.327 | .001 | 0.501 | 1.736 |
| 12 | 1.086 | 0.431 | .013 | 0.271 | 1.898 |
| 24 | 0.219 | 0.326 | .503 | −0.396 | 0.839 |
| Dose 2 | −0.185 | 0.164 | .262 | −0.493 | 0.127 |
Discussion
A single dose of oral gabapentin at 10 or 20 mg/kg was well tolerated in cheetahs, with complete administration success, and produced mild sedation across all time points within 24 hours. Mild ataxia and slower responses to outside stimuli were observed, with very few mild, self-limiting adverse events, indicating that gabapentin may be an effective tool for inducing mild sedation in cheetahs at the doses evaluated in this study.
Oral gabapentin in cheetahs is well absorbed, suggesting a higher bioavailability as compared to domestic felines.15 Domestic cats administered a single oral dose of gabapentin at 10 mg/kg reached a Cmax of 12.42 μg/mL (8.31 to 18.35), which is only half of what was achieved in this study.15 To date, no studies exist in felids describing efficacious plasma concentrations for anxiolysis; however, plasma concentrations remained above concentrations needed to treat neuropathic pain in a previously reported human study21 (5.4 μg/mL) for over 12 hours.
As a result of the sampling protocol in the current study, it was not possible to calculate all PK parameters (eg, t1/2 and area under the curve). The sampling times were selected based on published reports describing the PK of this drug in other species; however, it appears that this drug has a longer terminal phase compared to other species. The scarcity of later samples precluded calculation of PK parameters that rely on characterization of the terminal portion of the plasma concentration-time curve. However, the results of this study do suggest that the t1/2 of gabapentin in cheetahs is much longer than domestic cats.15,16 One possible explanation for the likely prolonged t1/2 is that the drug is cleared more slowly in cheetahs compared to other species. Another possible explanation is that the way in which the drug was administered led to a flip-flop phenomenon, whereby the rate of absorption is slower than the rate of elimination, and the terminal phase of the concentration curve is representative of absorption as opposed to elimination. Although additional sampling times to characterize the terminal portion of the curve following oral administration and IV administration data would be necessary to determine if this is the case, flip-flop kinetics has been suggested for gabapentin in other species.22–24 Peak plasma concentrations did not occur until 12 hours postadministration, in comparison to domestic felids, which occurs after less than 2 hours.15,16 Possible causes for a prolonged absorption phase could be due to the composition of diet items used for delivery of the medication or a normal species adaptation related to its natural history. Disease conditions, including gastritis, which is seen commonly as subclinical pathology in North American cheetahs under managed care, could also alter gastrointestinal motility and lead to a prolonged absorption phase.2 These findings indicate that dosing every 12 hours may be sufficient to maintain optimal gabapentin plasma concentrations to induce preferred levels of sedation in cheetahs if repeat dosing is necessary. However, further evaluation would be necessary to determine optimal intervals for multidose administration. In addition, peak plasma concentrations at 12 hours postadministration may guide timing strategies for the use of gabapentin as a premedication for stimulatory events. The differences between the findings of this research and domestic felid models emphasizes the need for species-specific studies.
Mean sedation scores remained within the mild sedation category for all time points at both dosages, with high variability between individual cheetahs. Both variability in temperament and gabapentin plasma concentrations from variation in absorption may have affected the level of sedation as has been seen in previous studies with domestic cats.11,15,16 Some cheetahs showed moderate sedation at the same time point and the same dosage as individuals with no observed sedation. This indicates that although a target dosage may serve as a helpful starting point, observation of an individual’s response may serve as a better indicator of what dosage is needed to achieve the desired level of sedation. In addition, mild-to-no adverse effects were observed, but further clinical evaluation (blood work and examinations postadministration) would be needed to fully evaluate safety.
A limitation of this study was the moderate-to-poor sedation score inter-rater agreement despite all scorers having clinical cheetah experience and zoological medicine residency training. Assessments were made entirely by video observation, which likely led to a decrease in sensitivity for observing subtle changes or overinterpretation of various behaviors depending on the observer. Sensitivity to mild changes in cheetah behavior also has the potential to be impacted by experience with the species as has been seen in feline studies with client-based observations.11 Other factors that had the potential to impact sedation scores included environmental and husbandry factors, such as the time of day and feeding regimes. Normal cheetah behavior, including resting during mid-day, may have exaggerated an otherwise mild sedation score, and conversely, temporal proximity to diet administration and visual exposure to the public had the potential to cause excitation. Lastly, the cat sedation scoring system was developed for domestic cats, and application to cheetahs may not appropriately capture behaviors associated with sedation in this species.
The need for a sparse sampling design due to the limitation of participants and compliance limited the scope of this study. Based on the findings of this study, future studies should also include additional later sampling time points to fully characterize the terminal portion of the concentration curve. This would allow for the determination of additional PK parameters, such as the t1/2 and the area under the curve. Additionally, this study was not a randomized, complete crossover study as all cheetahs were administered 10 mg/kg followed by a 2-to-3-month washout period before being administered 20 mg/kg. Future studies could consider a randomized, complete crossover study design given the unknown t1/2.
The findings of this study indicate that administration of gabapentin at a dosage of 10 to 20 mg/kg is an effective tool to induce mild sedation in cheetahs with minimal observed adverse effects. Administration at least 4 hours prior to a potentially stressful event may provide the best results, with the potential for individual variability. The use of gabapentin prior to a potentially stressful event can improve cheetah welfare by acting as an anxiolytic.
Acknowledgments
The authors thank Garrett Fraess, Matt Marinkovich, and Tess Rooney for sedation scoring; Nikki Bernardino for venipuncture assistance; and the cheetah husbandry teams at San Diego Zoo, San Diego Zoo Safari Park, and Wildlife Safari.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation or this manuscript.
Funding
Funds provided by the Pharmacokinetic Research Grant from the Veterinary Pharmacology Research Foundation and American Veterinary Medical Foundation. The project was also supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR001860.
ORCID
M. J. Peel https://orcid.org/0000-0003-0613-6497
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