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Pharmacokinetics of amitriptyline HCl and its metabolites in healthy African grey parrots (Psittacus erithacus) and cockatoos (Cacatua species).

Abstract: Amitriptyline, a tricyclic antidepressant, is used clinically to treat feather-destructive behavior in psittacine birds at a recommended dosage of 1-5 mg/kg PO q12-24h, which has been extrapolated from human medicine and based on anecdotal reports. The purpose of this pilot study was to describe the individual and population pharmacokinetic parameters of amitriptyline after a single oral dose at 1.5 mg/kg, 4.5 mg/kg, and 9 mg/kg in healthy African grey parrots (Psittacus erithacus, n = 3) and cockatoos (Cacatua species, n = 3). Three birds received an initial 1.5 mg/kg oral dose, and blood samples were collected for 24 hours at fixed time intervals. Serum concentrations of amitriptyline and its metabolites were determined by polarized immunofluorescence. After determining the initial parameters and a 14-day washout period, 2 African grey parrots and 1 cockatoo received a single oral dose at 4.5 mg/kg, and 3 cockatoos and 1 African grey parrot received a single oral dose at 9 mg/kg. Concentrations reached the minimum therapeutic range reported in people (60 ng/mL) in 4 of 10 birds (4.5 and 9.0 mg/kg). Concentrations were within the toxic range in 1 African grey parrot (9 mg/kg), with regurgitation, ataxia, and dullness noted. Serum concentrations were nondetectable in 3 birds (1.5 and 4.5 mg/ kg) and detectable but below the human therapeutic range in 3 birds (1.5 mg/kg and 9 mg/kg). Drug concentrations were continuing to increase at the end of the study (24 hours) in 1 bird. Elimination half-life varied from 1.6 to 91.2 hours. Population pharmacokinetics indicated significantly varied absorption, and elimination constants varied between species. Although amitriptyline appeared to be tolerated in most birds, disposition varies markedly among and within species, between the 2 genera, and within individual birds. The current recommended dosage of 1-5 mg/kg q12h in psittacine birds appears insufficient to achieve serum concentrations within the human therapeutic range and does not yield predictable concentrations. Results of this study suggest doses of up to 9 mg/kg may be necessary, although that dose may produce adverse events in some birds, and elimination half-life is sufficiently variable that dosing intervals are not predictable. Therapeutic drug monitoring combined with response to therapy is indicated to determine individual therapeutic ranges.

Key words: feather plucking, amitriptyline, tricyclic antidepressant, pharmacokinetic, avian, African grey parrots, Psittacus erithacus, cockatoo, Cacatua species.

Introduction

Tricyclic antidepressants (TCAs) are among the drugs used in companion-animal behavioral medicine and chronic pain management. (1,2) The TCAs are central nervous system (CNS) stimulants and. as a group, act by increasing concentrations of serotonin (5-HT), norepinephrine, or both in the CNS by blocking reuptake. In addition, long-term therapy apparently alters the postsynaptic monoamine oxidase receptor sensitivity. (3,4) In veterinary medicine, TCAs, including both clomipramine and amitriptyline, have been used for a myriad of conditions. Amitriptyline hydrochloride has been used for treatment of canine separation anxiety, (5) idiopathic cystitis in cats, (6) neuropathic pain in a falcon (Falco mexicanus), (7) as well as psychogenic feather picking in companion birds. (8,9)

Clinically, reported dosages for amitriptyline in companion birds have been extrapolated from anecdotal canine reports, human pharmacokinetic studies, and clinician experience. (10) In greyhounds, pharmacokinetic studies of oral and intravenous amitriptyline show extremely poor oral bioavailability (6%), suggesting that the current recommended oral dose does not reach the human plasma therapeutic range of 60-220 ng/mL. (11) However, results of a study examining oral and transdermal amitriptyline in cats indicated that therapeutic levels can be reached by oral administration but not by transdermal administration. (12) Mechanisms of TCA disposition vary markedly among species, rendering those species for which doses have been extrapolated more susceptible to adverse reactions. These include variable oral absorption, high protein binding, large distribution volume, long elimination half-life, and hepatic metabolism.

Amitriptyline has been used clinically in pet birds to control feather picking, as well as more severe self-mutilation behaviors. (10) The dosage of amitriptyline currently recommended in companion birds is 1-5 mg/kg q12-24h, but no pharmacokinetic data are available to determine whether therapeutic levels are reached. (13) Because of recent reports concerning poor bioavailability, and the potential for clinical use in managing chronic pain and feather picking, the validity of the current therapeutic dosage recommendations require scrutiny. The purpose of this pilot study was to determine the pharmacokinetics after a single dose of orally administered amitriptyline in cockatoos (Cacatua species) and African grey parrots (Psittacus erithacus) to establish whether therapeutic intervals are feasible with the current dosing range.

Materials and Methods

Data collection

Ten studies were performed in 6 birds: 3 cockatoos (1 umbrella cockatoo [Cacatua alba], 1 Goffin's cockatoo [Cacatua goffinii], and 1 sulphur-crested cockatoo [Cacatua galerita]) and 3 African grey parrots. Birds were part of the parrot research colony at the Schubot Exotic Bird Health Center, Texas A&M University (College Station, TX, USA). Each bird received up to 2 of the following doses: 1.5 mg/kg, 4.5 mg/kg, or 9.0 mg/kg (Table 1). One cockatoo and 2 African grey parrots initially received 1.5 mg/kg, based on a volume of distribution in people of 15 L/kg and a target plasma concentration of 100 ng/mL, which lies in the middle of the target range for people (60-220 ng/mL). (4) This dose also falls within the current recommended guidelines for treatment of feather-destructive behaviors in psittacine birds. (13) Samples were analyzed within 24 hours of collection to ensure concentrations were detectable and not toxic. Based on subtherapeutic concentrations at 1.5 mg/kg, the dose was modified such that 1 cockatoo and 2 African grey parrots received 4.5 mg/kg and 3 cockatoos and 1 African grey received 9.0 mg/kg. None of the birds were studied at all doses because of ethical concerns related to animal stress (Table 1). A minimum 14-day washout period was observed between doses if a bird received more than 1 dose. All doses were given orally as a solution of amitriptyline (Elavil, AstraZeneca, Wilmington, DE, USA), which was prepared by diluting the commercial intravenous solution with 5% dextrose in a 1:9 ratio. The intravenous solution, rather than a suspension of ground tablets, was used for formulation of the dose to better ensure even distribution of the active ingredients throughout the diluted oral solution. Oral solutions for each dose were prepared immediately before dosing, and birds were not fasted before drug administration. Each dose was deposited into the crop via a 14-Fr rubber feeding tube, and the tube was flushed with 3 mL of water before withdrawal from the crop. Blood samples for drug assay were collected from the jugular or basilic (wing) vein by venipuncture before and approximately 1, 2.5, 5, 7.5, 10, 17, and 24 hours after drug administration. Serum was harvested within 4 hours of sample collection and stored at 4[degrees]C until assayed. (14) Each bird was observed for evidence of drug loss or adverse drug effects for a 5-hour period after dosing and intermittently for the remainder of the 24-hour blood-collection period. Newspapers were placed under each cage to detect any drug that might be lost by regurgitation.

Determination of serum amitriptyline concentration

Amitriptyline concentration was quantitated in serum by a fluorescence polarization immunoassay (TDxFLx tricyclic antidepressant assay, Abbott Laboratories, Abbott Park, 1L, USA), which was validated for psittacine plasma. A major advantage of this assay for use in birds is the small sample volume (50 [micro]L) required. The coefficients of variation for the assay controls ranged from 2.9% to 8.5%. The quantitation limit of the assay was 20 ng/mL. The assay detects 4 primary TCAs and several related compounds. The assay does not discriminate between the parent compound and its major metabolite in people, which has up to 30% cross-reactivity. Concentrations of about 300 ng/ mL are considered toxic with this assay.

Data analysis

For each bird, amitriptyline concentrations at each sample time were subjected to noncompartmental analysis (Phoenix, St Louis, MO, USA), providing the elimination half-life ([t.sub.1/2]), area under the curve (AUC), mean residual time (MRT), maximum concentration ([C.sub.max]), and time to maximum concentration ([T.sub.max]) (Table 2). Because the drug was not administered intravenously, neither volume of distribution nor clearance could be determined; thus, the elimination curve may not reflect elimination (ie, it might represent a "flip-flop" model (15)) and will be referred to as disappearance (kd) in this report. Because of the significant amount of interindividual variation, a population pharmacokinetic model was generated for additional pharmacostatistics. The validity of the model was ranked based on the Akaike information criteria and Bayesian information criterion. (16) By the bootstrap technique, the bias and precision of the selected population pharmacokinetic model was examined, with 1000 bootstrap data sets selected and the final pharmacokinetic parameters calculated, including the absorption constant (tvKa), the volume (tvV), and the elimination constant (tvKe) (Table 3). (17)

Results

Most birds tolerated the oral administration of amitriptyline well, with the exception of one African grey parrot that vomited after administration of 9 mg/kg. Peak serum amitriptyline concentrations approximated 390 ng/mL in that bird, a concentration exceeding the toxic range established for people using this assay (300 ng/mL). That same bird had received 1.5 mg/kg (1/6 the dose), which generated peak serum concentrations of 39 ng/mL and no adverse effects (Table 2). Concentrations of 390 ng/mL were unexpected and exemplify the marked variability achieved in drug concentrations among birds (Figs 1 and 2). Adverse reactions observed in that bird, potentially attributable to amitriptyline, included regurgitation, both immediately after and at 15 hours after drug administration; ataxia ("wobbling" on the perch); and delayed responses to stimuli, such as persons approaching the cage.

Because of subtherapeutic or nondetectable concentrations, doses received by the birds were variable (Table 1). Four of six birds received >1 dose. In 3 of the 10 studies performed (at 1.5, 1.5, and 4.5 mg/kg), concentrations were not detectable. Serum drug concentration versus time curves best fit a 2-compartment model in those trials (n = 7) for which concentrations were sufficiently detectable to allow modeling (Figs 1 and 2). This included all cockatoos dosed at 4.5 mg/kg (n = 1) and 9.0 mg/kg (n = 3), and 1 African grey dosed at 4.5 mg/kg. Because results were so variable among birds even at the same dose, means were not calculated for pharmacokinetic parameters. The variability is best appreciated by comparing individual birds (Table 2; Figs 1 and 2).

In all but 1 of the 7 studies in which concentrations were detectable, serum amitriptyline concentrations were below the targeted range of 100 ng/mL, and in 3 of 7 studies, they were below the minimum therapeutic range (60 ng/mL) for people (Table 2). The time to [T.sub.max] was markedly variable, ranging from 1 to 24.5 hours; for the latter, concentrations may have continued to increase after the last sample was collected in that bird. The disappearance half-life was also variable, ranging from 1.5 hours to approximately 91 hours.

Because of the significant variation among species as well as individuals, a population model was developed. Evaluation of the population pharmacokinetic data (Table 3) show a marked difference in the rate of absorption (Ka) between African grey (185.0020 [+ or -] 0.0012/min) and cockatoo species (0.0039 [+ or -] 0.0026/min), with a similar total volume (tvV) and elimination constant rate (tv[K.sub.e]).

Discussion

In people, the therapeutic range for serum concentration of amitriptyline is 60-220 ng/mL. (4) We chose 100 ng/mL as the targeted range in this study because it was the middle of the human therapeutic range, and although not necessarily applicable to birds, provided a starting point. However, TCAs are characterized by marked variability in response in people. (18) Indeed, human patients have developed adverse cardiac effects at concentrations as low as 50-100 ng/mL, which has been correlated to polymorphisms of the cytochrome P450 enzymes CYP2D6 and CYP2C19. (19) Because of the lack of information regarding cytochrome P450 enzymes in avian species, we can only speculate whether species differences may relate to the variability observed.

The metabolite cis-hydroxy-amitriptyline was also detected by the polarized immunofluorescent assay used in this study. The magnitude of metabolite production in these birds cannot be addressed, but it is possible that no to little metabolites are produced. However, because the metabolite is active, the use of an assay that detects metabolites was more appropriate for this study. Despite an extensive literature search, we were unable to locate any information on minimum or maximum therapeutic concentrations of TCAs in any other species.

In people, amitriptyline is characterized by a volume of distribution of 15 L/kg and an oral bioavailability of 50%. (18) The calculated dose of 1.5 mg/kg based on that data is similar to that currently recommended for psittacine birds. However, that dose failed to generate concentrations that might be considered effective based on human therapeutic ranges. Indeed, at a dose of 4.5 mg/kg, concentrations were subtherapeutic in all birds studied. The final trials studied at a dose of 9.0 mg/ kg continued to yield subtherapeutic concentrations in 3 of 4 birds. Although above the therapeutic range in the fourth bird, the concentrations were sufficiently high to potentially cause adverse reactions.

Although variability was expected in data among birds and variability has been documented in people, the magnitude of the variability was not expected. Three birds were studied twice, allowing for some comparison of maximum drug concentrations for different doses (ie, dose-concentration relationship). In 1 bird (AG1) studied at 1.5 mg/kg (nondetectable) and 4.5 mg/kg (82 ng/mL), a reasonable dose-response relationship could not be determined. A second African grey (AG3) was studied at 1.5 mg/kg (39 ng/mL) and 9 mg/kg (390 ng/mL), resulting in a much higher than anticipated concentration at 9 mg/kg. This may reflect saturation of drug metabolizing enzymes. One cockatoo (C3) was studied twice, at 4.5 mg/kg (56 ng/mL) and 9.0 ng/mL (31 ng/mL), revealing a very poor dose-response relationship. Concentrations were continuing to increase in that bird at the last sampling time of 24 hours.

Clearly, the disposition of TCAs was quite variable in this study among psittacine birds--both among species within the same genus and between genera. Differences among African grey parrots appeared to be more pronounced than those among cockatoos in this study. Differences in rates of absorption may account for some of the variability in maximum concentrations, as was suggested by the marked differences in [T.sub.max] and [K.sub.a]. Additionally, concentrations in 1 bird peaked twice, suggesting delayed absorption. However, bioavailability and volume of distribution differences are also likely to contribute to variability in maximum concentrations. Birds were not fasted before drug administration in an effort to mimic clinical use of the drug, so it is possible that food interfered with absorption. Differences in dose formulation for each animal were not likely because the oral solution was made with an IV preparation to ensure dissolution and to facilitate equal distribution of the drug throughout the compounded preparation. Additionally, care was taken to mix each preparation well before administration. Differences in maximum concentration among the trials likely would have been greater had tablets rather than the intravenous solution been used to prepare the products. The magnitude of the differences in pharmacokinetic parameters between and within species at different doses suggests that further studies need to be performed, including a focus on bioavailability.

The disappearance of amitriptyline in the birds of this study is much faster than that reported for human patients (21 hours). (3,18,20) This may suggest that time to efficacy may not be as long in birds as it is in people. It may also indicate a need to dose animals twice daily, a dosing interval that may prove inconvenient for some bird owners. However, because 1 bird appeared to be absorbing drug at 24 hours, further studies are needed to fully characterize the rate of absorption and what effect a slow rate of absorption might have on dosing intervals.

This study did not address the efficacy of amitriptyline for use in feather-picking pet birds nor did it attempt to address a multiple-dosing regimen, which is needed to maximize effects of behavior-modifying drugs. However, our results suggest that the current recommended dose of 1-5 mg/kg for medicating pet birds is too low to achieve a serum concentration within the human therapeutic range in African grey parrots and cockatoo species. In this study, the highest concentration detected when birds were given a dose of 1.5 mg/kg was 39 ng/mL, which is below the human therapeutic range. These data would suggest that to reach 100 ng/mL, cockatoos might require 9.0 mg/kg, whereas African grey parrots require approximately 4.5 mg/kg. Results of this study suggest that genus or species differences might affect the pharmacokinetics of amitriptyline to the point that therapeutic failure may occur either because of failure to achieve effective concentrations or because of attainment of toxic drug concentrations. Therapeutic drug monitoring by a qualified laboratory may be crucial to therapeutic safety and efficacy. Finally, the results of this study also emphasize the hazards of tacit acceptance of pharmacokinetic and efficacy trials carried out in one species for use in a different species.

References

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(3.) Kukes VG, Kondratenko SN, Savelyava MI, et al. Experimental and clinical pharmacokinetics of amitriptyline: comparative analysis. Bull Exp Biol Med. 2009; 147(4):434-437

(4.) Normal TR, Burrows GD, Maguire KP. Pharmacokinetics of tricyclic antidepressants In: Angrist B, Burrows GD, Lader M, et al., eds. Recent Advances in Neuropsycho-Pharmacology: Selected Papers from the 12th Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Goteborg, Sweden, 22-26 June 1980. Philadelphia, PA: Elsevier, 2013:339.

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(6.) Kraijer M, Fink-Gremmels J, Nickel RF. The short-term clinical efficacy of amitriptyline in the management of idiopathic feline lower urinary tract disease: a controlled clinical study. J Feline Med Surg. 2003;5(3): 191-196.

(7.) Shaver SL, Robinson NG, Wright BD, et al. A multimodal approach to management of suspected neuropathic pain in a prairie falcon (Falco mexicanus). J Avian Med Surg. 2009;23(3):209-213.

(8.) van Zeeland YRA, Spruit BM, Rodenburg TB, et al. Feather damaging behavior in parrots: a review with consideration of comparative aspects. Appl Anim Behav Sci. 2009; 121 (2):75-95.

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(10.) Eugenio C. Amitriptyline HC1: clinical study for the treatment of feather picking. Proc Annu Conf Assoc Avian Vet. 2003; 133-135.

(11.) Norkus C, Rankin D, KuKanich B. Pharmacokinetics of intravenous and oral amitriptyline and its active metabolite nortriptyline in greyhound dogs. Vet Anaesth Analg. 2015;14:1-10.

(12.) Mealey KL, Peck KE, Bennett BS, et al. Systemic absorption of amitriptyline and buspirone after oral and transdermal administration to healthy cats. J Vet Intern Med. 2004; 18(1):43-46.

(13.) Hawkins MG, Barron HW, Speer BL, et al. Birds. In: Carpenter JW, ed. Exotic Animal Formulary. 4th ed. St Louis, MO: Elsevier; 2013:256-281.

(14.) Orsulak PJ, Sink M, Weed J. Blood collection tubes for tricyclic antidepressant drugs: a reevaluation. Ther Drug Monit. 1984;6(4):444-448.

(15.) Yanez JA, Remsberg CM, Sayre CL, et al. Flip-flop pharmacokinetics--delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv. 2011;2(5): 643-672.

(16.) Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978;6(2): 165-175.

(17.) Ette El, Williams PJ, Lane JR. Population pharmacokinetics III: design, analysis, and application of population pharmacokinetic studies. Ann Pharmacother. 2004;38(12):2136-2144.

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(19.) Steimer W, Zopf K, von Amelunxen S, et al. Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem. 2005;51(2):376-385.

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Marike Visser, DVM, Michelle M. Ragsdale, DVM, CVPP, CCRP, CVMA, and Dawn M. Boothe, DVM, PhD, Dipl ACVIM, Dipl ACVCP

From the Clinical Pharmacology Laboratory, Auburn University College of Veterinary Medicine, 1500 Wire Rd, 214 SRRC, Auburn, AL 36849, USA (Visser, Boothe); and the Pain Vet, 6202 Pebble Canyon Ct, Katy, TX 77450, USA (Ragsdale).

Table 1. Single doses of amitriptyline administered
orally to 6 birds in 10 pharmacokinetic studies in
individual birds.

                                        Dose, mg/kg
                             Bird
Bird                         no.    1.5   4.5   9.0

Umbrella cockatoo            C1     ND    --    D
Goffin's cockatoo            C2     --    --    D
Sulphur-crested cockatoo     C3     --    D     D
African grey parrot          AG1    ND    D     --
African grey parrot          AG2    --    ND    --
African grey parrot          AG3    D     --    D

Abbreviations: ND indicates tested at this dose, concentrations
were not detected in serum; --, not tested at this dose; D,
tested at this dose, concentrations were detected in serum.

Table 2. Pharmacokinetic parameters of amitriptyline in 6
psittacine birds after oral administration at 3 different doses.

Bird   Dose, mg/kg PO   [t.sub.1/2], h   [T.sub.max], h

AG1         4.5              1.6              2.5
AG3          9                15              5.5
AG3         1.5               91              5.0
C1           9               7.6              1.5
C2           9                --              10.0
C3           9                --              24.5
C3          4.5               7               2.5

Bird   [C.sub.max], ng/mL   AUC, min x ng/mL   MRT, h

AG1            82                23 985         4.2
AG3           390               263 135         18.5
AG3            39               166 662         132
Cl             90                 8557          11.7
C2             60                  --            --
C3             31                  --            --
C3             56                10 162         11.0

Abbreviations: [t.sub.1/2] indicates elimination half-life:
[T.sub.max], time to maximum concentration; [C.sub.max], maximum
concentration; AUC, area under the curve; MRT, mean residual
time; AG, African grey parrot; C, cockatoo; --, value could not
be calculated.

Table 3. Population pharmacokinetic parameters of amitriptyline
in 2 genera of psittacine birds after oral administration of a
single dose.

                                        Cockatoo

                               Mean                  95% CI

tv[K.sub.a], L/min    0.0039 [+ or -] 0.0026     -0.0014-0.0093
tvV, L                         0.07               0.058-0.087
tv[K.sub.e], L/min    0.0015 [+ or -] 0.0002      0.001-0.002

                                 African grey parrot

                               Mean                  95% CI

tv[K.sub.a], L/min   185.0020 [+ or -] 0.0012   185.001-185.005
tvV, L                        0.047                0.032-0.07
tv[K.sub.e], L/min    0.0011 [+ or -] 0.0003     0.0007-0.0019

Abbreviations: CI indicates confidence interval; tv[K.sub.a]
absorption constant; tvV, absorption volume; tv[K.sub.e],
elimination constant.
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Author:Visser, Marike; Ragsdale, Michelle M.; Boothe, Dawn M.
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Dec 1, 2015
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