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    Figure 1—

    Mean ± SD serum levetiracetam concentrations in 9 cats after oral administration of a single dose (500 mg) of a commercially available ER levetiracetam product (white circles) and a compounded ER levetiracetam formulation (black circles) and pooled CSF levetiracetam concentrations (white squares) in 3 cats for both preparations. There was a 1-week washout period between successive administrations. Samples for CSF evaluation were collected from 2 cats at 1, 2, 3, 4, 5, 7, 10, and 24 hours and from 1 cat at 14 and 19 hours. The minimum serum levetiracetam concentration considered therapeutic in humans (5 μg/mL) is indicated (dashed line).

  • 1. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:98619866.

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  • 20. Doheny HC, Ratnaraj N, Whittington MA, et al. Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy Res 1999;34:161168.

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Pharmacokinetics of a commercially available product and a compounded formulation of extended-release levetiracetam after oral administration of a single dose in cats

Erik R. Johnson1Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Amanda R. Taylor1Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Dawn M. Boothe2Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Heather L. Gray-Edwards3Department of the Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Randolph L. Winter1Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Doug R. Martin3Department of the Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36832.

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Abstract

OBJECTIVE

To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam.

ANIMALS

9 healthy cats.

PROCEDURES

Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis.

RESULTS

CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 μg/mL and 169 ± 51 μg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 μg/mL/mg and 1.10 ± 0.28 μg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE

The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 μg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.

Abstract

OBJECTIVE

To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam.

ANIMALS

9 healthy cats.

PROCEDURES

Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis.

RESULTS

CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 μg/mL and 169 ± 51 μg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 μg/mL/mg and 1.10 ± 0.28 μg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively.

CONCLUSIONS AND CLINICAL RELEVANCE

The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 μg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.

Levetiracetam is an antiepileptic drug that binds to a synaptic vesicle glycoprotein, SV2A.1,2 Although the exact mechanism of action for levetiracetam is unknown, it is thought that binding to SV2A results in the prevention of presynaptic calcium release and a decrease in neuronal excitation.1–3 Levetiracetam has been approved by the US FDA for use in the treatment of a variety of seizure disorders in humans.2,4–6 Levetiracetam is not currently approved by the US FDA for use in dogs and cats; however, it is often used in an extralabel manner to treat epilepsy in both species because of its rapid onset of action, effectiveness, tolerability, and safety, compared with these characteristics for other antiepileptics.7–13

The elimination half-life of levetiracetam in dogs and cats is approximately 3 hours.7,14 Thus, administration is required every 8 hours to maintain concentrations throughout the day that are above the minimum levetiracetam concentration found to be therapeutic in humans (5 μg/mL).15 Administration of drugs to dogs 3 times/d is inconvenient; thus, ER levetiracetam formulations have been evaluated for use in dogs.16,17 Investigators of 1 study16 found that oral administration of ER levetiracetam increased the elimination half-life to 4.5 to 5 hours. This would allow for twice-daily dosing, which would make it more feasible for owners to administer this drug. Recent reports18,19 support the oral administration of ER levetiracetam to cats, with a dosing interval of 12 hours, and even possibly 24 hours.

A current concern with the use of ER levetiracetam is that administration of even the smallest ER tablet (500 mg) can result in a dose that is substantially greater than the suggested dosage range (30 to 60 mg/kg, PO, q 12 h) for cats and dogs that weigh < 5 kg.16,17 To our knowledge, no studies have been conducted to evaluate the use of compounded formulations of ER levetiracetam in dogs and cats, which would allow for more appropriate doses in cats and small dogs.

An extremely limited number of studies have been conducted to evaluate the levetiracetam concentration in the CSF of any species. Studies of rats20 and humans21 have revealed that CSF concentrations of levetiracetam reach or exceed serum concentrations of levetiracetam, which suggests appropriate penetration of the blood-CSF barrier for this drug. However, no studies have been conducted to evaluate the CSF concentrations of levetiracetam in dogs or cats to determine whether the same situation exists for these species.

To the authors’ knowledge, no studies have been conducted to simultaneously evaluate serum and CSF concentrations of levetiracetam in cats after oral administration of a commercially available ER product or a compounded ER formulation. The objective of the study reported here was to compare the pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of a single dose of a commercially available ER product and a compounded ER formulation. We hypothesized that oral administration of compounded ER levetiracetam to cats would result in serum and CSF concentrations of levetiracetam significantly lower than those after oral administration of a commercially available ER levetiracetam product; that both the commercially available and compounded ER levetiracetam would maintain, for at least 12 hours after oral administration, concentrations found to be therapeutic in humans, which would allow for twice-daily dosing of cats; and that levetiracetam concentrations would be comparable in CSF and serum.

Materials and Methods

Animals

Nine cats from a research colony were selected for use in the study. Population size was determined on the basis of the ability to detect a difference of 50% in AUC0–∞ (anticipated variability, 25%; power, 80%) between the commercially available ER levetiracetam product and the compounded ER levetiracetam formulation. Cats were 8 months to 3 years old and had a minimum body weight of 2 kg (mean body weight, 3.4 kg; range, 2.8 to 5.46 kg). All cats were apparently healthy and had no abnormalities in results of a physical examination, neurologic examination, CBC, and serum biochemical analyses. Two cats were carriers of the genetic mutation for GM2 gangliosidoses; however, neither cat had clinical signs of neurologic disease. All procedures were approved by the Auburn University Institutional Animal Care and Use Committee.

Vascular access

Cats were anesthetized for placement of a catheter or VAP to provide vascular access for collection of blood samples. Cats received dexmedetomidine (0.005 to 0.04 mg/kg, IM) and ketamine hydrochloride (5 to 10 mg/kg, IM), which was followed by endotracheal intubation. Anesthesia was maintained with isoflurane (0% to 4%) combined with oxygen. A catheter (n = 3 cats) or VAP (6) was placed in a jugular vein, as described elsewhere.22,23 Catheters and VAPs were placed 24 hours before the start of the study. A VAP was placed only in cats > 1 year old.

Experimental procedures

A nonrandomized, nonblinded, prospective crossover study was performed. A single dose of a commercially available ER levetiracetam producta (500 mg) was orally administered to each cat. Blood samples were collected from all cats at 0, 10, 20, and 40 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours. Samples of CSF were collected from only 2 cats at 1, 2, 3, 4, 5, 7, 10, and 24 hours and from 1 other cat at 14 and 19 hours.

After a 1-week washout period, a single dose of a compounded ER levetiracetam formulationb (500 mg) was orally administered to each of the same 9 cats. Samples were collected at the same times as after administration of the commercially available ER levetiracetam product.

Sample collection

Blood samples (0.5 mL) were collected with a sterile syringe (via the catheter) or Huber needle (via the VAP). After each blood sample was collected, the catheter was flushed with 0.5 mL of sterile saline (0.9% NaCl) solution.c At the end of each sample collection, catheters and VAPs were flushed with 0.5 mL of heparinized (100 to 200 U/mL) saline solution.d Jugular catheters were maintained throughout the study and were removed soon after all CSF and blood samples were obtained for the compounded formulation. Vascular access ports were maintained subcutaneously after completion of the study for further pharmacokinetic studies in accordance with the protocol approved by the institutional animal care and use committee.

Samples of CSF were collected from the cisterna magna. Cats received an IV injection of dexmedetomidine and ketamine; cats were then endotracheally intubated, and anesthesia was maintained with isoflurane in oxygen. A sterile 25-gauge, 1.5-inch spinal needle was used to obtain 100 μL of CSF. When there was gross evidence of blood contamination of a CSF sample, a period of 5 minutes was allowed to elapse before a second attempt was made to collect CSF from the cisterna magna. All CSF samples were obtained in 1 or 2 attempts.

Blood and CSF samples were placed in centrifuge tubes.e Blood samples were allowed to clot at 21°C. Blood samples were centrifuged for 10 minutes at 1,500 × g; serum was harvested and refrigerated at 4°C until analysis. Samples of CSF were refrigerated at 4°C until analysis.

Measurement of serum levetiracetam concentrations

Levetiracetam was quantitated in feline serum by use of an immunoassay approved by the US FDA for use on human samples; the analysis was performed on a chemistry analyzer.16 The immunoassay was validated for use on feline serum by the Auburn University Clinical Pharmacology Laboratory.14 Upper and lower limits of quantitation were 100 and 2 μg/mL, respectively.16 Coefficient of variation for control samples was < 10% for a low concentration (7.5 μg/mL) and < 5% for a high concentration (75 μg/mL).

The instrument calibration for the CSF samples was determined on the basis of levetiracetam diluted in water; thus, validation was not performed in CSF. Control samples for CSF had the same concentrations as for the serum control samples. Coefficient of variation was < 5% for both low and high control concentrations.

Pharmacokinetic analysis

Serum levetiracetam concentration-versus-time data were subjected to noncompartmental analysis. The AUC0 was determined by use of the log-linear trapezoidal method. Values for Cmax and tmax were recorded. Mean concentration for the first 12 hours after administration and the concentration for the last sample collected were also recorded. Because there was a large variation in dose administered to each cat (mean ± SD, 155 ± 36.2 mg/kg; range, 93 to 204 mg/kg), Cmax corrected for dose and AUC0-∞ corrected for dose were calculated. Levetiracetam was not administered IV; therefore, clearance and volume of distribution could not be determined. Furthermore, the terminal component of the levetiracetam concentration-versus-time curve could not be determined to total elimination; thus, both terminal rate constant and half-life were reported as disappearance. Half-life was reported as the harmonic mean ± pseudoSD. Other parameters calculated included mean residence time and percentage of the AUC that was extrapolated from the terminal component of the curve. Relative bioavailability of levetiracetam was calculated as the ratio of the AUC0–∞ for the compounded formulation divided by the AUC0–∞ for the commercially available product. Finally, the amount of time serum concentrations were above the minimum serum levetiracetam concentration considered therapeutic in humans (5 μg/mL) was determined for each ER preparation and body fluid (serum and CSF).

Statistical analysis

Mean ± SD values (only the mean value for CSF) were determined by use of commercially available software.f A paired Student t test was used to compare pharmacokinetic parameters in serum between the compounded formulation and the commercially available product. The CSF samples obtained after administration of both the commercially available product and compounded ER levetiracetam formulations were pooled for analysis because full pharmacokinetic parameters could not be compared between the 2 preparations as a result of limited numbers of CSF samples obtainable for each cat. However, the time of collection of CSF samples for each cat was the same for both the compounded formulation and the commercially available product; thus, CSF concentrations of levetiracetam were compared by use of a paired Student t test. Values were considered significantly different at P < 0.05.

Results

Pharmacokinetics for serum samples

Levetiracetam pharmacokinetics for serum samples after oral administration of the ER levetiracetam preparations were determined (Table 1). The Cmax was significantly (P = 0.03) higher for the compounded formulation than for the commercially available product. The Cmax corrected for dose was also significantly (P = 0.02) higher for the compounded formulation than for the commercially available product. In addition, tmax was significantly (P = 0.01) less for the compounded formulation than for the commercially available product. There were no other significant differences between preparations for any other pharmacokinetic parameter.

Table 1—

Mean ± SD and 95% confidence interval (CI) values for pharmacokinetic parameters of levetiracetam in serum of 9 cats after oral administration of a single dose (500 mg)* of a commercially available ER levetiracetam product and a compounded ER levetiracetam formulation.

 Commercially available productCompounded formulation 
ParameterMean ± SD95% CIMean ± SD95% CIP value
Cmax (μg/mL)126 ± 33.0105–148169 ± 50.9135–2020.03
C12 (μg/mL)64.6 ± 8.958.7–70.456.6 ± 12.248.4–64.80.07
Clast (μg/mL)4.9 ± 3.22.8–7.05.2 ± 5.61.5–8.90.81
tmax (h)5.1 ± 1.64.0–6.13.1 ± 1.51.6–4.60.01
t1/2 (h)4.3 ± 2.03.0–5.65.0 ± 1.64.0–6.10.39
kd (h−1)0.19 ± 0.070.14–0.240.16 ± 0.100.10–0.220.45
AUC0–∞ (μg•h/mL)1,450 ± 2491,290–1,6101,650 ± 3581,410–1,8800.07
AUC0–∞D (μg•h/mL/mg)9.7 ± 1.68.7–10.711.1 ± 2.99.2–13.00.07
AUC0–∞exp (μg•h/mL)4.5 ± 5.31.1–8.05.9 ± 3.73.5–8.40.56
MRT (h)9.7 ± 2.38.2–11.39.7 ± 2.28.2–11.10.94
Cl/F (mg/kg)/(h•ng/mL)/kg112 ± 22.835–167101 ± 24.439–1850.11
Vd/F (mg/kg)/(ng/mL)/kg698 ± 353551–887719 ± 257242–1,1500.88
RFserum (%)NANA1.1 ± .211.0–1.3NA

Mean ± SD dose, 155 ± 36.2 mg/kg (range, 93 to 204 mg/kg)

Values were considered significantly different at P < 0.05.

AUC0–∞D = AUC0–∞ corrected for dose. AUC0–∞exp = Portion of AUC0–∞ that was extrapolated. C12 = Mean drug concentration for the first 12 hours after administration. Cl/F = Ratio of apparent total clearance to bioavailability. Clast = Drug concentration at the last measured time point. CmaxD = Cmax corrected for dose. kd = Disappearance rate constant. MRT = Mean residence time. NA = Not applicable. RFserum = Ratio of relative bioavailability for the compounded formulation to that for the commercially available product. t1/2 = Disappearance half-life. Vd/F = Ratio of apparent volume of distribution to bioavailability.

Mean ± SD amount of time that serum levetiracetam concentrations were above the minimal levetiracetam concentration considered therapeutic in humans (5 μg/mL) after administration of the commercially available ER product was 22.7 ± 1.7 hours (Figure 1). Similarly, mean amount of time that serum levetiracetam concentrations were maintained above the minimal levetiracetam concentration considered therapeutic in humans after administration of the compounded ER formulation was 22.9 ± 2.4 hours.

Figure 1—
Figure 1—

Mean ± SD serum levetiracetam concentrations in 9 cats after oral administration of a single dose (500 mg) of a commercially available ER levetiracetam product (white circles) and a compounded ER levetiracetam formulation (black circles) and pooled CSF levetiracetam concentrations (white squares) in 3 cats for both preparations. There was a 1-week washout period between successive administrations. Samples for CSF evaluation were collected from 2 cats at 1, 2, 3, 4, 5, 7, 10, and 24 hours and from 1 cat at 14 and 19 hours. The minimum serum levetiracetam concentration considered therapeutic in humans (5 μg/mL) is indicated (dashed line).

Citation: American Journal of Veterinary Research 80, 10; 10.2460/ajvr.80.10.950

Pharmacokinetics for CSF samples

Levetiracetam pharmacokinetics for CSF samples after oral administration of the ER levetiracetam preparations were determined (Table 2). Because of the limited number of CSF samples collected at each time point (1 or 2 samples/time point), mean and SD were not calculated. Pooled CSF samples were used to determine levetiracetam concentrations and used to create curves for visual comparison of time curves for serum and CSF concentrations of levetiracetam (Figure 1). Levetiracetam relative bioavailability in CSF (89%) was similar after oral administration of the compounded formulation and commercially available product. The ratio for levetiracetam relative bioavailability in CSF compared with in serum was 86% for the commercially available ER product and 85% for the compounded formulation.

Table 2—

Mean values for pharmacokinetic parameters of levetiracetam in CSF of cats after oral administration of a single dose (500 mg)* of a commercially available ER levetiracetam product and a compounded ER levetiracetam formulation.

ParameterCommercially available productCompounded formulation
Cmax (μg/mL)123150
Clast (μg/mL)7.24.6
C24 (μg/mL)50.357.5
tmax (h)4.03.0
t1/2 (h)4.33.7
kd (h−1)0.160.18
AUC0–∞ (μg•h/mL)1,2501,410
AUC0–∞exp (μg•h/mL)3.51.8
MRT (h)8.98.9
RFCSF (%)NA0.89
RFCSF:serum (%)0.860.85

Samples of CSF were collected from 2 cats at 1, 2, 3, 4, 5, 7, 10, and 24 hours and from 1 cat at 14 and 19 hours.

C24 = Mean drug concentration for the first 24 hours after administration. RFCSF = Ratio of relative bioavailability of levetiracetam in CSF for the compounded formulation compared with that for the commercially available product. RFCSF:serum = Ratio of the relative bioavailability of levetiracetam in CSF compared with that for levetiracetam in serum for each ER preparation.

See Table 1 for remainder of key.

Discussion

Results of the study reported here indicated that the serum concentration-versus-time curves after oral administration of the same dose of a compounded ER levetiracetam formulation and a commercially available ER levetiracetam product were comparable. Both ER preparations maintained serum levetiracetam concentrations in healthy cats for at least 12 hours after oral administration that were above the minimum levetiracetam concentration considered therapeutic in humans. This would allow for a 12-hour dosing interval of either preparation for cats, and potentially even a 24-hour dosing interval for some cats. Furthermore, the present study revealed that CSF concentrations of levetiracetam paralleled serum concentrations of levetiracetam after oral administration of both preparations; therefore, serum levetiracetam concentrations should be able to serve as a reasonable surrogate for CSF levetiracetam concentrations. The CSF levetiracetam concentrations were similar to serum levetiracetam concentrations in this study, which may have been attributable to the fact that levetiracetam is a small, neutral molecule without substantial protein binding that allows distribution across the blood-brain barrier in cats. Similarly, levetiracetam concentrations in serum mirror those in CSF of rats, for which the CSF-to-serum levetiracetam concentration ratio is 1.09, which indicates ready penetration of levetiracetam across the blood-brain barrier in that species.20

The Cmax for levetiracetam after oral administration of the compounded ER formulation was higher than that after oral administration of the commercially available ER product, even when Cmax was corrected for dose. Additionally, Cmax was reached more rapidly (ie, smaller tmax) after oral administration of the compounded ER formulation. Both of these differences suggested that levetiracetam was released more rapidly from the compounded ER formulation than from the commercially available ER product, which is an indication of the difficulties in developing a compounded formulation that perfectly imitates a commercially available product. Although compounded ER levetiracetam formulations would be intended for use in companion animals, such formulations currently are designed on the basis of ER products for humans, who have metabolic, anatomic, physiologic, and biochemical characteristics of the gastrointestinal tract that differ from those of cats.24 Because ER formulations are not developed on the basis of the feline gastrointestinal tract, bioavailability and absorption rates for the compounded formulation of the present study may differ from those of other ER levetiracetam formulations.

Creating ER compounds is more complex than creating immediate-release formulations and can lead to alterations in pharmacological parameters of anti-epileptic drugs in humans.25 When creating ER compounds, pharmaceutical companies use different ER technology that will change absorption of antiepileptic drugs.25 The compounded ER levetiracetam capsules were made by only 1 compounding pharmacy for the study reported here. It is not clear whether a common recipe for ER formulations is used by all compounding pharmacies. For that reason, we can conclude that only the compounded ER levetiracetam formulatione from that specific pharmacy would be appropriate for twice-daily administration. It would be prudent to evaluate compounded ER levetiracetam formulations made by other compounding veterinary pharmacies to determine whether the same pharmacokinetics are consistent for various compounded preparations.

Furthermore, multiple generic forms of ER levetiracetam products currently are available, and a comparison of the pharmacokinetics of generic forms of levetiracetam in cats is also necessary. Generic ER levetiracetam has been compared with brand name ER levetiracetam in dogs, and generic ER levetiracetam maintained minimum concentrations considered therapeutic in humans for at least 12 hours, although there was pharmacokinetic variability among the various ER levetiracetam formulations.17 However, obstacles in the formulation of ER compounds and differences between commercially available and compounded ER levetiracetam preparations are clinically irrelevant because both ER levetiracetam preparations of the present study resulted in a mean concentration at 12 hours after administration that was above the minimum concentration considered therapeutic in humans. Disappearance half-life and mean residence time of both ER levetiracetam preparations were prolonged, compared with the mean ± SD disappearance half-life and mean residence time for immediate-release levetiracetam (2.95 ± 0.95 hours and 5.65 ± 1.25 hours, respectively),14 which further supported use of a 12-hour dosing interval and efficacy of the ER levetiracetam preparations evaluated in the present study.14

Serum levetiracetam concentrations were above the minimum concentration considered therapeutic in humans for approximately 23 hours after oral administration of both ER levetiracetam preparations. Use of a 12-hour dosing interval, and maybe a 24-hour dosing interval for some cats, was supported on the basis of the variation in the data for the study reported here. Similar results were obtained in another study18 in which commercially available ER levetiracetam was orally administered to cats and minimum therapeutic concentrations were maintained for up to 21 hours. Additionally, long-term oral administration of commercially available ER levetiracetam has maintained minimum levetiracetam concentrations considered therapeutic in humans for 24 hours,19 which would support a 24-hour dosing interval. Because variations in serum levetiracetam concentrations exist in cats administered ER levetiracetam preparations, serum levetiracetam concentrations ideally should be measured in epileptic cats at 12 and 24 hours after levetiracetam administration to help determine whether once- or twice-daily administration of levetiracetam is appropriate for each cat. Realistically, adjustment of the dose of ER levetiracetam should be made on the basis of the clinical response of each epileptic patient. Simply maintaining minimum therapeutic anticonvulsant concentrations does not always correlate with improvements in seizure control. Epileptic patients often require therapeutic concentrations greater than the minimum therapeutic concentration, which may suggest use of a 12-hour dosing interval for adequate seizure control despite the fact therapeutic levetiracetam concentrations are maintained for at least 24 hours.26

To our knowledge, the study reported here was the first one conducted to evaluate CSF concentrations of levetiracetam in cats, and results suggested penetration of the blood-brain barrier after oral administration of ER levetiracetam, regardless of the preparation. Although mean and SD values for CSF samples were not determined, pooled CSF levetiracetam concentrations mirrored serum levetiracetam concentrations after oral administration of both ER levetiracetam preparations; these results suggested that appropriate CSF levetiracetam concentrations were maintained for at least 12 hours after oral administration. Additionally, comparison of levetiracetam concentrations in CSF and serum revealed that both ER levetiracetam preparations had high relative bioavailability. This indicated that monitoring of serum levetiracetam concentrations can be used as an accurate evaluation of CSF levetiracetam concentrations in cats.

The study reported here had several limitations. Therapeutic serum levetiracetam concentrations have not been determined in cats, and therapeutic CSF levetiracetam concentrations have not been determined in any species. For those reasons, suitable feline serum and CSF levetiracetam concentrations were extrapolated on the basis of established serum levetiracetam concentrations considered therapeutic in humans, which represented a drastic oversimplification. Because therapeutic levetiracetam concentrations have not been determined for cats, medication adjustments for epileptic cats should be made on the basis of seizure control and levetiracetam-associated adverse effects. Levetiracetam concentrations are still of value for the confirmation of levetiracetam absorption, measurement of chronic changes in levetiracetam concentrations that may be associated with alterations in seizure control, and establishment of whether once- or twice-daily dosing is appropriate in a particular cat. Additionally, although CSF levetiracetam concentrations were determined in the cats of the present study, those concentrations would not necessarily correlate with levetiracetam penetration into the brain interstitium and synapses, which are the source of epileptogenesis. Evaluation of brain biopsy specimens with microscopic synaptic sampling techniques would be needed to determine actual levetiracetam concentrations in the brain interstitium. For obvious ethical reasons, it is unlikely that those concentrations will be determined.

Another limitation of the present study was the limited number of CSF collections at each time point. This did not allow us to determine mean and SD levetiracetam concentrations for each of the ER levetiracetam preparations. Although the mean and variability of these values was not known, the results were considered to be promising on the basis of the comparison with serum levetiracetam concentrations. Future studies are warranted to provide more complete pharmacokinetic data for levetiracetam in the CSF.

Mean ± SD dose of ER levetiracetam administered to the cats (155 ± 36.2 mg/kg) was above the recommended dose for oral administration (30 to 60 mg/kg, q 12 h). Additionally, the dosing range was extremely variable (93 to 204 mg/kg) because of the inability to modify the commercially available ER levetiracetam tablet without altering its ER properties. A population of cats of more uniform size would help prevent this disparity in future studies. Studies on administration of compounded ER levetiracetam formulations are needed to determine whether similar pharmacokinetic patterns are evident for lower and less variable doses. Although the safety of ER levetiracetam was not evaluated in the present study, no obvious adverse effects were noted. In another study18 conducted to evaluate the same dose of ER levetiracetam in cats, only nonserious adverse effects were rarely noted. It has been reported12 that 18% of cats receiving long-term administration of a low dose (10 to 25 mg/k, q 8 h) of immediate-release levetiracetam developed adverse effects, which were mild and transient. Thus, it would appear that future safety studies with long-term administration of high doses of levetiracetam are not needed to monitor adverse effects.

Acknowledgments

This manuscript represents a portion of the requirements for a Master of Science degree submitted by Dr. Johnson to the Department of Biomedical Sciences at Auburn University.

Supported by the Scott-Ritchey Research Center and Wedgewood Pharmacy.

The authors declare there were no conflicts of interest.

Presented as an oral presentation at the American College of Veterinary Internal Medicine Forum, Seattle, June 2018.

The authors thank Roy Harmon for assistance with analysis of samples and Jessica Cannon and Melissa Korbely for assistance with collection of samples.

ABBREVIATIONS

AUC

Area under the curve

AUC0–∞

Area under the curve from time 0 to infinity

Cmax

Maximum concentration

ER

Extended release

tmax

Time to maximum concentration

VAP

Vascular access port

Footnotes

a.

Keppra XR, 500-mg tablets, Lupin Pharmaceutical, Baltimore, Md.

b.

Levetiracetam XR, 500-mg slow-release formulation in a gelatin capsule, provided by Wedgewood Pharmacy, Swedesboro, NJ.

c.

B Braun Medical Inc, Bethlehem, Pa.

d.

Heparin sodium injection USP, 1,000 U/mL in 0.9% NaCl, Sagent Pharmaceuticals, Schaumburg, Ill.

e.

BD Vacutainer sterile 4.0-mL plastic tubes, BD Biosciences, Franklin Lakes, NJ.

e.

Phoenix WinNonlin, version 7.0, Certera Corp, Princeton, NJ.

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Contributor Notes

Dr. Johnson's present address is Department of Neurology and Neurosurgery, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061.

Dr. Taylor's present address is Department of Neurology and Neurosurgery, MedVet Columbus, 300 E Wilson Bridge Rd, Columbus, OH 43085.

Dr. Gray-Edwards' present address is Department of Radiology, UMass Medical School, University of Massachusetts, Worchester, MA 01655.

Dr. Winter's present address is Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

Address correspondence to Dr. Johnson (vetofthebay@gmail.com).