Pharmacokinetics of compounded intravenous and oral gabapentin in Hispaniolan Amazon parrots (Amazona ventralis).
Key words: gabapentin, neuropathic pain, pharmacokinetics, avian, Hispaniolan Amazon parrot, Amazona ventralis
Pain perception is typically an adaptive response to avoid additional tissue damage and encourage wound healing. (1) Pain sensation typically occurs because of activation of nociceptor afferent nerves by actual or potential, tissue-damaging stimuli. Conditions that induce chronic pain are maladaptive and are associated with a diminished quality of life. (2) Neuropathic pain is a manifestation of chronic pain that arises with damage to the somatosensory system. (2) It often induces persistent or paroxysmal pain sensations that may or may not be associated with a stimulus. (1) Neuropathic pain is associated with beak trimming in poultry and is suspected in 2 cases of traumatic and self-induced injuries in a prairie falcon (Falco mexicanus) and a Senegal parrot (Poicephalus senegalus). (4-8) Additional hypothesized causes for neuropathic pain include chronic orthopedic diseases, spinal injury, chronic feather destructive behavior, self-mutilation, abnormal feather growth, neurotropic viral diseases (ie, herpesviruses, bornaviruses, and encephalitis viruses), and neoplasia or following surgery or radiation therapy.
Alleviation of neuropathic pain often presents a challenge in both human and veterinary medicine. In human medicine, patients typically do not respond to anti-inflammatory medications and often develop a resistance or insensitivity to opioids. (1) Adverse effects associated with administering these medications long term, as well as the controlled status of most opioids by the US Drug Enforcement Administration, can also limit their use. Pharmacologic treatment recommendations are often multimodal and, in people, include a combination of antidepressants, gabapentin or pregabalin, topical anesthetics, opioids, and tramadol. (2) Treatment of neuropathic pain in veterinary medicine often mimics protocols used in human medicine. Indeed, the few reports communicating treatment of suspected neuropathic pain in avian patients describe the use of gabapentin as part of the therapeutic regimen. (4,7,8)
Gabapentin was originally used as an adjunctive therapy for refractory seizures. (9) It has since been shown to alleviate neuropathic pain as well as to potentially decrease acute postoperative pain. (9) Gabapentin is a structural analogue of the neurotransmitter [gamma]-aminobutyric acid. It does not, however, appear to serve as a [gamma]-aminobutyric acid agonist or alter [gamma]-aminobutyric acid binding, reuptake, or degradation. (10) Although the mechanism of action of gabapentin is not completely understood, the drug likely binds to the [alpha]2[delta] subunit of voltage-gated calcium channels that then act presynaptically to decrease the release of excitatory neurotransmitters. (11) In people, gabapentin is not protein bound, has variable dose-dependant oral
bioavailability, and has a wide tissue distribution. (12-16) It is not metabolized and is excreted unchanged in the urine and feces. (12,13) Few side effects are reported for gabapentin, but these include drowsiness, dizziness, weakness, headache, nausea, ataxia, weight gain, and amblyopia. (17)
Multiple reports have been published evaluating the pharmacokinetics of gabapentin in veterinary species. (12,13,18-26) In the species studied, distinct differences exist in the absorption, (12,13,26) volume of distribution, (12,13,25) metabolism, (12,13) and half-life (13,21-23,25,26) of gabapentin. To date, there have been no pharmacokinetic studies published, to our knowledge, in avian patients. Therefore, doses used clinically are extrapolated from other veterinary species studied; however, differences in metabolism between species may affect effective doses and dosing intervals. The purpose of this study was to evaluate the plasma pharmacokinetic parameters for intravenous and oral gabapentin after a single dose in Hispaniolan Amazon parrots (Amazona ventralis) to extrapolate a dose and dosing interval for additional studies.
Materials and Methods Study birds and housing
Eight Hispaniolan Amazon parrots (ages 14-19 years) housed at the Knoxville Zoological Gardens (Knoxville, TN, USA) were used for the project. The birds were randomly allocated into 1 of 3 groups. They had been in residence at the zoo for 5 months before the start of the study and had previously been part of a closed research collection at the University of Tennessee, College of Veterinary Medicine, before transition to the Knoxville Zoo. The birds had no previous pertinent medical concerns and had not been used in a research project for 8 months before initiation of this project. The birds were housed indoors in various sized, wire cages with either 1 or 2 birds in each cage. Their diet consisted of a pelleted food and various fresh fruits and vegetables. The housing and diet were not changed during the study. The birds were judged healthy based on results of physical examinations and hematologic parameters (packed cell volume, total solids, and estimated white blood cell count) within 1 month before the start of the study. The University of Tennessee Institutional Animal Care and Use Committee approved the experimental protocol.
The birds were monitored throughout the duration of the study for side effects, including alterations in body position, activity, and appetite.
Gabapentin preparation and administration
A gabapentin intravenous suspension (50 mg/ mL) was compounded by a pharmacist at the University of Tennessee, College of Veterinary Medicine, compounding pharmacy by dissolving gabapentin bulk powder (Tokyo Chemical Industry Co Ltd, Tokyo, Japan) into sterile water for injection. The solution was then drawn up with a 22-[micro]m filter and placed into an empty sterile glass vial with a second 22-[micro]m filter. An aliquot of the solution was submitted for anaerobic, aerobic, and fungal culture after preparation. The suspension was protected from light, stored at 4[degrees]C for 7 days until use, and mixed thoroughly by inversion before administration. The intravenous suspension was administered with a 25-gauge needle and a 1-mL syringe into the basilic vein at 30 mg/kg to group 1 (2 birds). A gabapentin oral suspension (50 mg/mL) was compounded as previously described with a commercial suspending agent (Ora-Blend, Fagron, Rotterdam, Netherlands) and 300-mg gabapentin capsules (Teva Pharmaceutical Industries Ltd, Petach Tikva, Israel). (27) The suspension was stored at 4[degrees]C for 5 days until use and mixed thoroughly by inversion before administration. The oral suspension was administered via 14-Fr metal feeding needles and a 1-mL syringe at 10 mg/ kg to group 2 (3 birds) and 30 mg/kg to group 3 (3 birds).
To test stability of the intravenous gabapentin suspension, the suspension was prepared as described above with the same batch of bulk powder protected from light and stored at 4[degrees]C. After gentle inversion, 2 aliquots (samples A and B) were removed for analysis just after preparation (day 0) and on days 7 and 14. The samples were stored at -80[degrees]C until analysis.
Sample collection and handling
A total of 0.3 mL of blood was collected from the right jugular vein from each bird by with a 1-mL syringe and 22-gauge needle immediately before drug administration and then at 5, 15, and 30 minutes and 1.5, 3, 6, 9, 12, and 24 hours after drug administration. The samples were immediately placed into lithium-heparin tubes and centrifuged. The plasma was decanted and stored at -80[degrees]C until analysis.
Determination of gabapentin concentration
Analysis of gabapentin in plasma samples and compounded suspension were conducted with reversed-phase, high-performance liquid chromatography. The system consisted of a 2695-separations module and a 2475-fluorescence detector (Waters, Milford, MA, USA). Separation was attained on a Waters Atlantis T3, 4.6 X 250 mm (5 pm) proceeded by a 5-pm Atlantis T3 guard column. The mobile phase was a mixture of acetonitrile and 50 mM potassium phosphate dibasic buffer (pH 5.0). The mixture was pumped at a starting gradient of 53% and 47% buffer and acetonitrile, respectively, and was adjusted to 49% and 51% over 15 minutes and back to initial conditions over 5 minutes. The flow rate was 1.1 mL/min. The fluorescence detector was set at an excitation of 300 and an emission of 500 with the gain at 10X. The column was at ambient temperature, which was 22[degrees]C.
Gabapentin was extracted from plasma samples with the solid-phase extraction method of Mercolini et al. (28) Previously frozen plasma samples were thawed and vortex mixed; 100 [micro]L was transferred to a clean tube; after which, 15 [micro]L of internal standard (vigabatrin 10 [micro]g/mL) was added followed by 1 mL of 0.1 N HCl. This mixture was loaded onto a preconditioned MCX cartridge (Waters). Samples were eluted with 2 mL ammonia: water: acetonitrile (5:13:82) and evaporated to dryness with nitrogen gas. Samples were redissolved in 100 [micro]L water and subjected to a derivatization process.
Standard curves for plasma analysis were prepared by spiking untreated plasma with gabapentin, which produced a linear concentration range of 0.5-100 [micro]g/mL. Average recovery was 97% for gabapentin. Intra-assay variability ranged from 1.0% to 5.4%, whereas interassay variability ranged from 0.4% to 11% for gabapentin. The lower limit of quantification was 0.5 [micro]g/mL.
Standard curves for compounded gabapentin were prepared by spiking saline with gabapentin, which produced a linear concentration range of 0.5-100 [micro]g/mL. The average recovery was 97% for gabapentin.
Compartmental analysis of the concentration versus time data was conducted by nonlinear mixed effects modeling, as implemented with Monolix software (Monolix 4.3, Lixoft SAS, Orsay, France). Monolix was also used to simulate the concentration-time profile for different dosing scenarios with the best-fit model. The simulations predicted the dose required for a desired exposure profile in the average animal. In addition, noncompartmental analysis of the individual data was completed with standard pharmacokinetic software (WinNonlin Phoenix, version 6.3, Pharsight, St Louis, MO, USA). Summary noncompartmental analysis pharmacokinetic parameters were reported as the arithmetic means and coefficients of variability. Terminal half-life was reported as the harmonic mean and pseudostandard deviation.
The best-fit oral model was used to simulate the concentration-time profiles resulting from different dosing scenarios. These simulations were used to propose reasonable dosages.
Aerobic, anaerobic, and fungal culture results of the intravenous suspension were negative. Mild sedation, characterized by sitting fluffed with both eyes intermittently closed, was observed within 2-3 minutes after drug administration in both birds used in the intravenous study. The birds were easily arousable and responded appropriately (vocalized, attempted to bite) if manipulated. The sedation lasted approximately 20-30 minutes. No additional side effects were observed for the duration of the study.
A 2-compartment open model best fit the intravenous data, whereas a 1-compartment open model with first-order absorption best fit the oral data. The calculated pharmacokinetic parameters are listed in Tables 1 and 2. The plasma concentration versus time profiles after oral and intravenous administration of gabapentin are shown in Figures 1 and 2. The evaluation of dosing scenarios by computer simulation showed that a dose of 15 mg/kg PO q8h would be a reasonable dosing starting point (Figure 3) in Hispaniolan Amazon parrots, based on effective plasma concentrations reported for human patients.
The calculated concentration and percentage of nominal concentration were reported for the intravenous suspension stability study on days 0, 7, and 14 (Table 3). Sample A for day 0 was lost during the extraction process.
To our knowledge, reports describing the pharmacokinetics of gabapentin have not been published in avian species. In this study, we determined the pharmacokinetics after a single intravenous dose (30 mg/kg) and 2 oral doses (10 mg/kg, 30 mg/kg) in Hispaniolan Amazon parrots.
Pharmacokinetic parameters have been described for other veterinary species, including rodents, (12,13) dogs, (12,13,22) cats, (25) calves, (19-21) and horses. (23,26) Systemic availability was high after oral administration in our study (80%-89%), which was similar to reports in rodents, dogs, and cats. (13,25) This result indicated that oral dosing was an appropriate route of administration in Hispaniolan Amazon parrots. The systemic availability was greater than values reported for horses (16%). (23) The intravenous half-life was slightly shorter than previous reports in cats and dogs (2.9 and 2.8 hours, respectively), and similar to findings in rodents. (13,25) The oral half-life was longer than it was in dogs, cats, and rodents (2.2, 2.9, and 1.7 hours respectively) but shorter than it was in horses and calves (7.7 and 11 hours, respectively). (13,21,23,25) The oral formulation may exhibit flip-flop kinetics in Hispaniolan Amazon parrots, which would explain the apparent difference in half-life between the intravenous and the oral routes of administration; however, the differences in oral half-life may be secondary to the small number of animals in our study and potential data variability. A larger, single-dose study needs to be performed to elucidate this difference. Time to maximal plasma concentration was similar to previous reports in rodents, dogs, monkeys, cats, and horses, (12,13,22,23,25,26) but lower than it was in calves (8-9 hours). (19-21) Maximum plasma concentration per dose administered was similar to values reported for greyhound dogs (0.65-0.84 meg/ mL), (22) and maximum plasma concentration for the 10 mg/kg PO study was similar to previous reports in cats and greyhound dogs (7.98 and 8.54 mg/L, respectively) but higher than it was in calves (2.97 mg/L). (21,22,25) The volume of distribution was high in this study, indicating wide distribution to body tissues. This is comparable to other species, including monkeys, cats, and horses (0.679, 0.65, 0.809 L/kg, respectively) (13,23,25); however, the volume of distribution in rats was higher (1.16-1.44 L/ kg), and in dogs, it was lower (0.158 L/kg) (13) than what was seen in this study.
A mild, transient sedation was seen during the study after intravenous injection of gabapentin. The sedation lasted 20-30 minutes, and no additional side effects were observed. Sedation is rarely noted as a side effect in other species, including horses after 20 mg/kg IV infusion, and an overdose of 110 mg/kg PO in a prairie falcon (Falco mexicanus). (4,23) The sedation seen in the horses lasted up to 2.5 hours, and the horses were noted to be easily arousable. The prairie falcon was initially given 11 mg/kg oral gabapentin with no side effects observed for 57 days before overdose.
Following a 10X overdose (110 mg/kg), diarrhea, ataxia, and a decreased mental alertness were observed. The next day the bird was agitated and hyperesthetic. In people, sedation is the most commonly reported side effect; however, it does not appear to be dose dependant and is transient in most patients. (16,17) Unlike veterinary patients, however, people possess a saturable gastrointestinal transport mechanism that may preclude against accidental overdose. (16) Although appreciable side effects were not observed with oral gabapentin administration in this study, additional studies need to be performed to determine the safety of multiple oral doses of gabapentin in avian patients.
Effective plasma concentrations for alleviation of neuropathic pain for veterinary species have not been established. In people, a serum concentration of >2 mg/L was associated with a reduced frequency of seizures (29); however, other studies report a range as high as 2-20 mg/L. (30) Serum drug monitoring in people is difficult because of the interindividual variation in the pharmacokinetics, dose-dependant bioavailability, and short half-life. (30) Dosage recommendations in people, therefore, are typically based off a dose (milligrams) per patient rather than serum drug monitoring. (18) Doses recommended for antiepileptic therapy are similar to doses recommended for neuropathic pain. (31) The human literature suggests a dosage of 1800 to 3600 mg/d (600-1200 mg q8h) for alleviation of neuropathic pain. (31) To our knowledge, there have been no reports of plasma concentrations associated with an 1800 mg/d gabapentin dosage (600 mg q8h) in people. Therefore, human pharmacokinetic parameters reported for gabapentin (12) were used to calculate plasma concentrations for an 1800 mg/d dosage (600 mg q8h). (25) The calculated plasma concentrations for alleviation of neuropathic pain in people are between 4 and 8 mg/L. (25)
In the parrots, administration at 10 and 30 mg/ kg PO resulted in gabapentin plasma concentrations above an 8 mg/L target for 0.2 and 4.3 hours, respectively. Administration at 30 mg/kg IV resulted in concentrations above an 8 mg/L target for 4 hours. Based on these results, we performed a simulation of different dosing schemes. These data suggested that a dosage of 15 mg/kg q8h may be appropriate to maintain analgesic plasma concentrations within a 4-8 mg/L target window in an average Hispaniolan Amazon parrot during the treatment period. Given the small sample size in this study (n = 2 and n = 3), care must be used with clinical extrapolation of the results because the birds used may represent outliers rather than be representative of the pharmacokinetics in a population of Hispaniolan Amazon parrots. Additional studies need to be performed to determine the pharmacokinetics of a single dose of gabapentin in a larger number of Hispaniolan Amazon parrots, to evaluate the pharmacokinetics of multiple doses, and to establish effective plasma concentrations with pharmacodynamic studies.
In addition, the limitation of small sample size does not allow proper estimation of interindividual variability. The estimated variability (Table 1) reported for the study was consistently small, especially for the intravenous results; however, the estimates of variability were likely affected by the small sample size. In addition, in most other species studies, gabapentin is not metabolized, except in dogs, where it is metabolized to N-methylgabapentin. (12,13) During this study, we did not measure gabapentin metabolites, so we were unable to determine whether gabapentin was metabolized in Hispaniolan Amazon parrots.
In this study, we compounded the oral gabapentin suspension despite having a commercially available human suspension. This was because the commercially available suspension contains xylitol (Neurontin, Pfizer, New York, NY, USA), which has been shown to be toxic to canine patients. (32) There have been no reports of xylitol toxicity in avian patients to date; however, the commercially available suspension was not used to avoid any potential toxicity. When a drug is modified or compounded for administration, ideally, there must be some assurance that the compounded medication retains the same quality as the original commercial formulation. A previous study showed that the compounded oral gabapentin suspension remained stable at 4[degrees]C for 91 days in a plastic prescription bottle when prepared as described. (27) The intravenous suspension in this study showed a percentage of nominal concentration or potency of 100% for at least 7 days when prepared as described. On day 14, sample B had a potency of 94%. These results indicate that the intravenous suspension administered during the pharmacokinetic study was stable when used at 7 days after preparation. However, a limitation in the stability study is that the initial intravenous gabapentin suspension was not used for analysis. Instead, a separate suspension was prepared from the same batch of bulk powder from the same manufacturer. Because there can be significant individual batch variation, the stability analysis may not be representative of the initial intravenous suspension used in the study. Compounding the intravenous suspension for clinical use is not recommended because sterility of the compound cannot be assured after preparation.
Acknowledgments: We thank the Knoxville Zoo for providing care for parrots, Terry Stevens for drug compounding assistance, and Misty Bailey and Dr Marcy Souza for editing assistance. This project was supported by a grant from the University of Tennessee Fund for Companion Animal Research.
Katherine Baine, DVM, Dipl ABVP (Avian), Michael P. Jones, DVM, Dipl ABVP (Avian), Sherry Cox, MS, PhD, and Tomas Martin-Jimenez, DVM, PhD, Dipl ACVCP, Dipl ECVPT
From the Departments of Small Animal Clinical Sciences (Baine, Jones) and Biomedical and Diagnostic Sciences (Cox, Martin-Jimenez), College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. Present address (Baine): Animal Emergency and Specialty Center, 10213 Kingston Pike, Knoxville, TN 37922, USA.
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Table 1. Population pharmacokinetic parameter estimates of Hispaniolan Amazon parrots. intravenous (n = 2) and oral (n = 3) doses of gabapentin in Parameter CV% estimate SE, % estimate SE % Intravenous, 30 mg/kg (n = 2) Clearance (L/h*kg) 0.304 5 3.7 86 [V.sub.c] (L/kg) 0.313 16 2.2 >1000 Q (L/h*kg) 0.727 32 3.7 >1000 [V.sub.p] (L/kg) 0.338 15 1 >1000 Residual error 13.7 21 Oral. 10-30 mg/kg (n = 6) [k.sub.a] (1/h) 0.517 39 30.36 72 [V.sub.d]/F (L/kg) 0.765 38 11.51 159 Cl/F (L/h*kg) 0.357 13 27.34 40 Residual error (constant) 1.5 11 Abbreviations: CV indicates coefficient of variation; [V.sub.c], apparent volume of the central compartment; Q, intercompartmental clearance; [V.sub.p], plasma volume; [k.sub.a], absorption rate constant; [Vs.ub.d]/F, volume of distribution corrected for bioavailability; Cl/F, clearance corrected for bioavailability. Table 2. Noncompartmental parameters (means) of oral (n = 3) and intravenous (n = 2) doses of gabapentin in Hispaniolan Amazon parrots. 10 mg/kg Oral Parameters (n = 3) CV% [AUC.sub.0-8], mg X h/L 26.87 13.77 [AUC.sub.0-12], mg X h/L 28.82 13.05 [AUC.sub.0-24], mg X h/L 30.87 12.85 [AUC.sub.0-[infinity]], mg X h/L 31.52 12.71 [AUC.sub.0-[infinity]]/D 3.15 12.71 [C.sub.0], mg/L [C.sub.max], mg/L 7.29 22.01 [C.sub.max]/D, mg/L 0.73 22.01 [T.sub.max], h 2.00 43.30 HL, h 5.41 14.40 MRT, h 5.11 10.60 [V.sub.z]/F, L/kg 2.50 17.91 Cl/F, L/h X kg 0.321 12.20 Time, >4 mg/L 4.10 Time, >8 mg/L 0.20 F, % 89.12% 30 mg/kg Oral Parameters (n = 3) CV% [AUC.sub.0-8], mg X h/L 68.39 36.33 [AUC.sub.0-12], mg X h/L 77.47 37.49 [AUC.sub.0-24], mg X h/L 84.86 37.40 [AUC.sub.0-[infinity]], mg X h/L 85.60 37.40 [AUC.sub.0-[infinity]]/D 2.85 37.40 [C.sub.0], mg/L [C.sub.max], mg/L 16.08 23.63 [C.sub.max]/D, mg/L 0.54 23.63 [T.sub.max], h 2.50 34.64 HL, h 3.74 12.00 MRT, h 5.24 37.15 [V.sub.z]/F, L/kg 2.21 58.15 Cl/F, L/h X kg 0.396 46.45 Time, >4 mg/L 7.79 Time, >8 mg/L 4.34 F, % 80.68% 30 mg/kg IV Parameters (n = 2) CV% [AUC.sub.0-8], mg X h/L 100.68 14.05 [AUC.sub.0-12], mg X h/L 103.75 14.39 [AUC.sub.0-24], mg X h/L 105.81 13.95 [AUC.sub.0-[infinity]], mg X h/L 106.10 13.79 [AUC.sub.0-[infinity]]/D 3.54 13.78 [C.sub.0], mg/L 97.68 10.27 [C.sub.max], mg/L [C.sub.max]/D, mg/L [T.sub.max], h HL, h 1.55 2.51 MRT, h 2.34 4.89 [V.sub.z]/F, L/kg 0.64 16.26 Cl/F, L/h X kg 0.285 13.79 Time, >4 mg/L 5.81 Time, >8 mg/L 3.96 F, % Abbreviations: CV indicates coefficient of variation; AUC, area under the curve; [C.sub.0], concentration at time 0; [C.sub.max], maximum plasma concentration; [C.sub.max]/D, maximum plasma concentration per dose administered; [T.sub.max], time to maximum plasma concentration; HL, half life; MRT, mean residence time; [V.sub.z]/F, apparent volume of distribution of the area fraction of the dose absorbed; Cl/F, plasma clearance per fraction of the dose absorbed; F, bioavailability. Table 3. Stability analysis of compounded intravenous gabapentin suspension. The nominal concentration was 50 mg/mL. Calculated Nominal Day/sample concentration, mg/mL concentration, % 0/A NA NA 0/B 50 100 7/A 50 100 7/B 50 100 14/A 50 100 14/B 47 94 Abbreviation: NA indicates not analyzed because lost in extraction process.
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|Title Annotation:||Original Study|
|Author:||Baine, Katherine; Jones, Michael P.; Cox, Sherry; Martin-Jimenez, Tomas|
|Publication:||Journal of Avian Medicine and Surgery|
|Date:||Sep 1, 2015|
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