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Pharmacokinetics of levetiracetam in healthy Hispaniolan Amazon parrots (Amazona ventrails) after oral administration of a single dose.

Abstract: Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots (Amazona ventralis), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 [micro]g/mL and 95.1 [micro]g/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14 100 and 28 820 mg X min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored.

Key words: seizure disorders, anticonvulsive, levetiracetam, pharmacokinetics, plasma concentrations, avian, Hispaniolan Amazon parrot, Amazona ventralis


Seizure disorders represent a sizable proportion of neurologic morbidity in avian patients. Principal causes are nutritional disorders, trauma, toxicosis, cardiovascular disease, neoplasia, metabolic disease, and idiopathic epilapsy. (1) Idiopathic epilepsy is a diagnosis of exclusion and has been reported presumptively in peach-faced lovebirds (Agapornis roseicollis), red-lored Amazon parrots (Amazona autunmalis), cockatiels (Nymphicus hollandicus), double yellow-headed Amazon parrots (Amazona oratrix), and mynah birds (Gracula religiosa). (2, 4) Generalized tonic-clonic seizures are the most common type of seizures in birds. In addition, focal-onset seizures and psychomotor seizures have been reported. (1) Currently, no reliable, fast-acting, effective, long-term antiepileptic drugs are licensed for use in avian medicine. Avian anticonvulsive treatments have been poorly described, and few pharmacokinetic (PK) studies have been performed, with mixed results. (1,5,6) Phenobarbital is currently the most frequently prescribed anticonvulsant in small-animal medicine, primarily because of its efficacy, long half-life, and low expense. However, a recent study showed that oral phenobarbital at a dose of 20 mg/kg had low efficacy in African grey parrots (Psittacus erithacus) and failed to reach therapeutic levels from poor oral absorption, rapid elimination, or both. (5) Furthermore, phenobarbital has been associated with adverse effects, including sedation, polyuria, polydipsia, polyphagia, facial pruritus, bone marrow dyscrasias, and coagulopathies. (7)

Levetiracetam is a newer, structurally novel, antiepileptic drug that has demonstrated efficacy for both partial and generalized seizures in human patients. (8) The mechanism of action of levetiracetam is not entirely understood, but it has been postulated (9) to involve inhibition of excitatory neurotransmitter release by binding to the synaptic vesicle protein SV2A, thereby modulating calciumdependent exocytosis of neurotransmitters. It also suppresses the inhibitory effect of [Zn.sup.2+] on gamma-aminobutyric acid and glycine-gated currents. (10) In addition to its anticonvulsant effects, it is neuroprotective when administered prophylactically to rodents with experimentally induced cerebral ischemia and head trauma. (11)

In humans, clinical trials have revealed levetiracetam effective as the sole treatment for control of myoclonic and primary, generalized, tonic-clonic seizures in patients with idiopathic epilepsy. It also has minimal effects on the disposition of other antiepileptic drugs and can be used synergistically, making it an ideal adjuvant medication for patients with refractory epilepsy. (9)

Pharmacokinetic studies of levetiracetam in humans, dogs, and cats have shown the drug to have excellent oral absorption, with an estimated bioavailability of about 100%, but a short half-life. (12-15) Preclinical studies in humans have illustrated a high safety margin and, currently, it is preferred in critical or geriatric patients because of minimal hepatic metabolism and primary renal excretion. (12)

The PKs of levetiracetam in parrots have not been studied; therefore, guidance on dosages is unavailable. The purpose of this investigation was to examine the PKs of orally administered levetiracetam in Hispaniolan Amazon parrots (Amazona ventralis). Although no definitive therapeutic range has been established, doses that achieve serum concentrations of 5.5 to 45 [micro]g/mL in humans have been shown to be effective. (16) Our hypothesis was that doses of 50 mg/kg and 100 mg/kg administered orally would produce plasma concentrations of levetiracetam in the human therapeutic ranges of 5.5 to 45 [micro]g/mL. Information from this experiment can be used to guide treatment and dosage recommendations for birds affected by seizure disorders.

Materials and Methods


Twenty adult Hispaniolan Amazon parrots, with a mean [+ or -] standard deviation body weight of 287 [+ or -] 19 g and a range of 263-321 g, were obtained from a colony maintained at Louisiana State University. Tap water and commercial, pelleted psittacine diet (Kaytee Exact, Kaytee Products, Chilton, WI, USA) were available ad libitum. Birds were considered clinically healthy based on unremarkable medical histories and results of physical examination and complete blood cell counts. The protocol for the study was approved by the Louisiana State University Institutional Animal Care and Use Committee.

Birds were randomly assigned by computer software to 2 treatment groups consisting of 10 animals. One group was administered 50 mg/kg, and the second group was administered 100 mg/kg of a commercially available levetiracetam oral suspension (Levetiracetam 100 mg/mL, Morton Grove Pharmaceuticals, Morton Grove, IL, USA) by crop gavage tube followed by 3 mL of water. The volume of levetiracetam administered to each bird ranged between 0.13 and 0.16 mL for the 50 mg/kg dose and between 0.26 and 0.32 mL for the 100 mg/kg dose. Because of the size of the animals, each treatment group was further subdivided into 2 blood sampling groups (n = 5/group). For blood collection, a 26-gauge 5/8-inch needle on a 1-mL syringe was used to collect 0.4 mL from the jugular, ulnar, or metatarsal veins and was placed into heparinized tubes (BD Microtainer tubes, Franklin Lakes, NJ, USA). From the first sampling group, blood was collected at 0, 30, 120, 360, 600, and 840 minutes after drug administration. From the second sampling group, blood was collected at 15, 60, 240, 480, 720, and 960 minutes after drug administration. Total amount of blood taken from each bird was no more than 2.6 mL (ie, < 1% bodyweight). Heparinized tubes were immediately placed on ice and subsequently centrifuged for 5 minutes at 1163g. Plasma was harvested and stored at -70[degrees]C until analyzed for levetiracetam concentration. Each bird's demeanor was monitored each time plasma samples were obtained and for 24 hours after levetiracetam administration.

Drug quantification

The concentration of levetiracetam in plasma was determined with an ARK diagnostic immunoassay (ARK Diagnostics Inc, Sunnyvale, CA, USA) on a Siemens Dimension Xpand (Siemens USA, New York, NY, USA) general chemistry analyzer. The system was calibrated with the ARK diagnostic levetiracetam calibrator kit. According to the manufacturer's documentation, the assay is selective for levetiracetam and does not cross-react with a variety of epileptic drugs or other compounds that are routinely coadministered and had <6.6% cross-reactivity with 2-pyrrolidone-V-butyric acid, a known metabolite when spiked at 250 mcg/mL to 50 mcg/mL levetiracetam. (17) The upper and lower limits of quantitation were 100 mcg/mL and 2 mcg/mL, respectively. The coefficient of variation (CV) was <10% for the low and <5% for the high range controls. The validity of the assay for quantitation of levetiracetam in parrot blood was confirmed by adding known concentrations of levetiracetam to drug-free parrot serum. The intraday and interday accuracies and the precision of independently prepared, quality-control samples at 7.5, 30, and 75 mcg/mL were within 10% of the nominal values with CV [less than or equal to] 10%. (17)

PK analysis

Parameter estimation: The PK parameters were estimated, from a noncompartmental analysis of levetiracetam plasma concentration after single perioral (PO) dose of 50 or 100 mg/kg, with WinNonlin Professional software (version 5.2, formerly Pharsight Corporation, now Certara USA, St Louis, MO, USA). Parameters included maximum plasma drug concentration ([C.sub.max]), time at maximum plasma drug concentration ([T.sub.max]), area under the plasma drug concentration-time curve from time 0 to infinity ([AUC.sub.0-[infinity]]), terminal half-life ([t.sub.1/2]), apparent volume of distribution/ bioavailability (Vd/F), and total systemic clearance/bioavailability (CL/F). The [AUC.sub.0.[infinity]] was estimated by the log-trapezoidal method and extrapolating exposure from last measurement concentration to infinity method, [T.sub.max] was visualized on the drug concentration-time profiles, and [C.sub.max] and [AUC.sub.0-[infinity]]> were normalized to dose. (18)

Pharmacokinetic modeling--multiple dosing: The effect of dose and multiple dosing on the time profile of the levetiracetam plasma concentration was estimated assuming linear and stationary kinetics with a conventional PK model to simulate different dose levels (10, 25, 50, 100, 200, and 500 mg/kg) and frequencies (single [q24h], 2 [q12h], and 3 (q8h) doses). Modeling and simulation beyond the observed data of 50 and 100 mg/kg assumed linear and stationary PKs and provided drug concentration-time profile estimates that could be used to design novel dosing schedules and to test hypotheses related to exposure-response relationships. A naive pooled data approach, with all levetiracetam plasma concentrations from the 50 and 100 mg/kg single-dose treatment groups, were used to evaluate different PK models with WinNonlin. A conventional 1-compartment PK model (1CM) following first-order, extravascular input (absorption; ka) and a first-order, elimination rate ([k.sub.el]) were fitted to the observed levetiracetam plasma concentration ([C.sub.p])-time (t) data, described by the following equation:

[C.sub.p] = {([FD.sub.0][k.sub.a])/[V([k.sub.a] - [k.sub.el])]} x [exp( - [k.sub.el]t) - exp( - [k.aub.a]t)]

where [D.sub.[omicron]] is the dose, and F is the oral bioavailability. The mean PK parameters generated by noncompartmental analysis were used as the initial parameter estimates. Levetiracetam has shown complete absorption, that is, near-100% bioavailability, in cats, dogs and humans (14,19,20); however, species differences in oral bioavailability are not uncommon. The oral bioavailability was not determined and could not be estimated in this species; therefore, it was fixed to 100%, that is, F = 1.0, and CL and V were shown as a function of bioavailability. Model fit was discriminated based on goodness of fit (visual inspection), the Akaike information criterion, and the sum of squares. (21, 22) Based on model fit, the dose and frequency of administration were simulated, and [k.sub.a] = 0.04, [k.sub.el] = 0.005, V = 0.8, and F = 1.0 were fixed.


Mean PK parameters were estimated by non-compartmental analysis. The concentration-time profiles (Fig 1) resembled characteristic absorption with a [C.sub.max] of 61.0 [micro]g/mL, a [T.sub.max] of 95.1 mg/L at 60 minutes, a [t.sub.1/2] of 2.38 and 2.37 hours, a Vd/F of 0.807 and 0.773 L/kg, and an AUC of 14 100 and 28 820 mg x min/L, with a Cl/F of 3.65 and 3.60 mL/min per kg, respectively (Table 1). Similarities in [C.sub.max]/[D.sub.o], AUC/[D.sub.o], [t.sub.1/2], Vd/F, and Cl/F suggest that levetiracetam exhibits linear kinetics from 50 to 100 mg/kg, which was comparable to other levetiracetam studies.

The goal of the PK modeling was to describe the PK behavior of levetiracetam plasma concentration in birds and to predict optimal dosing schedules for future studies, based on preliminary in vitro studies that suggested an effective concentration of 5.5 [micro]g/mL. These data suggest that 50 mg/kg (q8h) and 100 mg/kg (q12h) dosing achieved levetiracetam plasma concentrations greater than the 5.5 [micro]g/mL target range (Fig 2B and C). These data also predict that dose levels [less than or equal to] 500 mg/kg, assuming linear and stationary kinetics, would not achieve concentrations >5.5 [micro]g/mL for the entire dose period (Fig 2A). Interestingly, these data also suggest that a dose [greater than or equal to] 25 mg/kg q8h, assuming linear and stationary kinetics, may also achieve 5.5 [micro]g/mL (Fig 2C).

Plasma concentrations were >5.5 [micro]g/mL for up to 9.4 and 12 hours, respectively, suggesting that an oral dose of 50 mg/kg q8h or an oral dose of 100 mg/kg q12h would be sufficient to maintain systemic drug levels at a range found to be clinically relevant in humans (Fig 1).


Treatment options for seizure disorders in birds are limited, which necessitates the need to identify new and effective antiepileptic drugs. Several novel, second-generation, antiepileptic drugs have been developed that appear to be effective and well tolerated in humans, dogs, and cats. (14,15,23,24) Although the results of these studies can be extrapolated to birds, because of their high metabolic rates and high transit times, differences in pharmacodynamics or PKs can be profound. This study is the first, to our knowledge, to demonstrate oral levetiracetam dosages in birds that result in targeted blood concentrations of levetiracetam. Results provide compelling evidence for the safe use of this drug in psittacine birds at doses of 50 and 100 mg/kg.

Although therapeutic ranges for plasma concentrations of levetiracetam have not been defined in avian medicine, the human range is from 5.5 to 45 [micro]g/mL, based on the typical dosage of 500 to 1500 mg q12h. (25) The results of this study suggest that levetiracetam at 50 mg/kg PO q8h or 100 mg/kg PO q12h would achieve and maintain plasma concentrations in Hispaniolan Amazon parrots. Furthermore, studies in rodents suggest that the pharmacodynamic responses and antiepileptogenic activity of levetiracetam may have the potential to persist long after its elimination from plasma because of its propensity to accumulate in high concentrations within cerebrospinal fluid (CSF). (26) Concentrations of drugs in the CSF, especially antiepileptic drugs, have been shown to be kinetically indistinguishable and can act as indices of drug concentrations at their central sites of action. (26) A study in rats showed the half-life of levetiracetam in the CSF to be approximately twice that of it in plasma. (26) The high CSF concentration was thought to be due to the rapid transport mechanism of levetiracetam across the blood-brain barrier.

In humans, levetiracetam rapidly distributes into peripheral tissues, with concentrations approximating those in the blood. Uptake is independent of multidrug transporters, p-glycoprotein, or the multidrug-resistant family proteins, which have been shown to be problematic in other antiepileptic drugs. (7) It rapidly and readily crosses the blood-brain barrier, entering both extracellular and the CSF compartments. Furthermore, in other species, levetiracetam brain concentrations have been shown to increase linearly and dose dependently and do not display brain-region specificity, with comparable distribution noted within both the extracellular fluid of the hippocampus and the frontal cortex. (7)

The safety and efficacy of levetiracetam in humans have been evaluated extensively. (25, 27) Multiple, double-blinded, placebo-controlled trials conducted in both the United States and Europe have established its safety and efficacy as an adjunct treatment for refractory or partial seizures in adults and children. (28, 29) Pharmacokinetic studies in dogs, rodents, and rabbits (Lepus curpaeums) that achieved target plasma ranges of (5.5-15) [micro]g/mL did not report any adverse effects. (15,19,23) The most common adverse effects associated with the administration of levetiracetam in humans are CNS related and include somnolence, fatigue, dizziness, nervousness, hyperkinesia, and headaches. (10) None of the birds that were administered levetiracetam showed any adverse effects in this study. However, only 1 dose was administered.

Although the exact mechanism of levetiracetam metabolism and excretion has not been studied specifically in birds, it is almost exclusively excreted by the kidneys in all other species in which it has been evaluated. In dogs, 50% 90% is excreted unchanged within the urine. (30) Similarly, in humans, it is eliminated mostly unchanged by the kidneys, with the remaining drug metabolized primarily through enzymatic hydrolysis in the bloodstream, liver, and other tissues. It is through this primary renal excretion that levetiracetam is thought to minimize the risk of liver disease and other hepatic drug interactions. (8) Although the bioavailability (F) was not determined in this study, the bioavailability in multiple species has been estimated to be ~100% or F ~ 1.0. (14,18,19) The Cl/F of levetiracetam of 3.65 and 3.60 mL/kg per minute were similar to those in other studies, with an approximately 98% total excretion within 24 hours. (30) Unlike other antiepileptic drugs, levetiracetam and gabapentin are not metabolized by the cytochrome P450 pathway in the liver. (10) In human trials, the PKs of levetiracetam and its primary metabolite LO57 are unaffected by mild-to-moderate hepatic impairment. However, severe hepatic impairment results in twofold to threefold increases in the half-lives of levetiracetam and L057 and in the AUC values, with total body clearance reduced by >50%. These changes were thought to be the consequence of concurrent mild-to-moderate renal impairment (hepatorenal syndrome) rather than liver dysfunction. (12)

In humans, the renal clearance of levetiracetam and its metabolite L057 correlate directly with glomerular filtration rate. The AUC values increase with decreasing renal function. In patients with mildly to moderately impaired renal function, AUC values can be nearly twice those of individuals with normal renal function. (12) Therefore, dosage reduction is suggested in patients with impaired renal function. Although the PKs of levetiracetam in birds with renal disease is beyond the scope of this study, we suggest reducing dosages in birds suspected to have renal disease.

Levetiracetam is thought to have a low potential for drug interactions because it is not protein bound in the blood and is not metabolized in the liver. (10) Experimentally, levetiracetam has been associated with numerous pharmacodynamic interactions with other antiepileptic drugs, although the mechanism for such interactions are poorly understood. In clinical trials, the anticonvulsant efficacy of levetiracetam has been shown to be substantially and synergistically enhanced by GABAergic drugs. (29)

In humans, levetiracetam has shown to have marginal interaction with the PKs of other anticonvulsive drugs. (8) In placebo-controlled trials in adult patients with partial onset seizures receiving adjunctive levetiracetam, there was no evidence of PK drug interactions between levetiracetam and carbamazepine, clobazam, clonazepam, diazepam, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, valproic acid, vigabatrin, or zonisamide. (29, 31) However, in some human trials, mild changes in PKs of levetiracetam have been observed. Levetiracetam appears to have a slightly higher clearance rate when CYP enzyme-inducing antiepileptic drugs, such as phenobarbital, were coadministered. These interactions did not appear to be clinically significant, and dosage adjustments were not required. (29) However, results of a similar study in dogs showed a rapid decrease in the half-life of levetiracetam when coadministered with phenobarbital at therapeutic levels. (32) These results were not observed in other species, such as domestic cats or rats. (8,33) Fortunately, previous oral absorption studies have shown phenobarbital to be a poor choice in avian seizure control. (5) Further studies are needed to understand the underlying PK effects on levetiracetam described with the concomitant use of other antiepileptic drugs.

Although this study describes only the PK of levetiracetam in Hispaniolan Amazon parrots, a clinical case report described the management of seizures with levetiracetam in an African grey parrot (Psittacus erithacus) with therapeutic blood monitoring. (34) This parrot continued with generalized seizures, despite treatment with phenobarbital and potassium bromide. After treating with levetiracetam to a target range of 5.5 to 45 [micro]g/mL, the frequency of seizures decreased substantially. During the 20-month follow-up period, subsequent clusters of seizures were controlled by adjusting levetiracetam and zonisamide dosages and by adding clonazepam and gabapentin to the treatment plan. (34) The highest dose of levetiracetam in that parrot consisted of 100 mg/kg PO q8h. (34)

The lack of clinically observed adverse effects, in conjunction with favorable PK and its potential efficacy, make the use of levetiracetam a reasonable option for seizure management in parrots. Pharmacokinetic results suggest a dose of 50 mg/kg administered q8h and 100 mg/kg q12h will provide targeted concentrations that, at least in humans, should be effective in preventing and controlling seizures. However, individual variation does occur, suggesting that clinical practitioners not only monitor levetiracetam effectiveness in seizure control but also monitor individual plasma levels and change the dose or frequency accordingly. Our PK data suggest that, at least with oral dosing, levetiracetam might be a useful adjunct or primary treatment for psittacine birds with epilepsy; however, further studies and clinical trials must be done.

Acknowledgments: We thank the South Alabama Bird Club, the Gulf South Bird Club, the Kaytee Avian Foundation, and the Association of Avian Veterinarian Grant Foundation for their financial support.


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Rodney Schnellbacher, DVM, Hugues Beaufrere, Dr Med Vet, PhD, Dipl ECZM (Avian), Dipl ABVP (Avian), Robert D. Arnold, PhD, Thomas N. Tully Jr, DVM, MS, Dipl ABVP (Avian), Dipl ECZM (Avian), Joerg Mayer, DVM, MS, Dipl ABVP (ECM), Dipl ECZM (Small Mammal), and Stephen J. Divers, BVetMed, DZooMed, Dipl ECZM (Elerpetology and Zoo Health Management), Dipl ACZM, FRCVS

From the Department of Small Animal Medicine and Surgery (Zoological Medicine), University of Georgia, Athens, GA 30602, USA (Schnellbacher, Mayer, Divers); the Health Sciences Centre, Ontario Veterinary College, University of Guelph, 50 Stone Rd, Guelph, ON NIG 2W1, Canada (Beaufrere); Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA (Arnold); and LSU School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr, Baton Rouge, LA 70803, USA (Tully).

Table 1. Pharmacokinetic parameter estimates for levetiracetam
administered to adult Hispaniolan Amazon parrots (n = 20) at 50
mg/kg (n = 10) and 100 mg/kg (n = 10) PO. Parameters were
estimated following a noncompartmental analysis of each parrot's
individual, drug concentration-time curve with WinNonlin.

                                             50 mg/kg

Parameter                               Estimate     SD

[C.sub.max], [micro]g/mL                61         14
[C.sub.max], dose/L                     1.22       0.28
[T.sub.max], min                        60 (a)     NA
Terminal slope, [lambda]z/min           0.00485    0.00113
Half-life [t.sub.1/2], h                2.38       0.86
AU[C.sub.0--[infinity], mg X min/L      14 100     3510
AU[C.sub.0-[infinity], dose/min per L   282        56.5
Cl/F, mL/min per kg                     3.65       0.56
[V.sub.d]/F, L/kg                       0.807      0.303

                                             100 mg/kg

Parameter                               Estimate      SD

[C.sub.max], [micro]g/mL                95.1        41.4
[C.sub.max], dose/L                     0.951       0.414
[T.sub.max], min                        60 (a)      NA
Terminal slope, [lambda]z/min           0.0047      0.00107
Half-life [t.sub.1/2], h                2.37        0.78
AU[C.sub.0--[infinity], mg X min/L      28 820      3510
AU[C.sub.0-[infinity], dose/min per L   282         35.1
Cl/F, mL/min per kg                     3.6         0.46
[V.sub.d]/F, L/kg                       0.773       0.193

Abbreviations: SD indicates standard deviation; [C.sub.max],
maximum plasma drug concentration; [T.sub.max], time at maximum
plasma drug concentration; AU[C.sub.0-[infinity], area under
plasma drug concentration-time curve from lime 0 to infinity;
Cl/F, total systemic clearance/bioavailability; [V.sub.d]/F,
apparent volume of distribution/bioavailability.

(a) [T.sub.max] estimated after fitting a 1-compartment PK (1CM)
model with first-order absorption to data to avoid bias related
to sampling schedule.
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Title Annotation:Original Studies
Author:Schnellbacher, Rodney; Beaufrere, Hugues; Arnold, Robert D.; Tully, Thomas N., Jr.; Mayer, Joerg; Di
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Sep 1, 2014
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