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Therapeutic phenobarbital levels in cats

Delamaide Gasper JA, Barnes Heller HL, et al. Therapeutic serum phenobarbital concentrations obtained using chronic transdermal administration in healthy cats. J Feline Med Surg. 2015 Apr; 174(4):359-63.

Chronic administration of any oral medication to a feline patient is often challenging for many owners, and the longer a medication must be administered, the more resistant the patient may become.  Only a few medications commonly used in cats are known to reach therapeutic serum levels with application of a transdermal preparation. Phenobarbital is the most commonly used anti-epileptic drug in cats with seizures of non-metabolic etiology, and has been shown to control seizures in 93% of cats when therapeutic serum levels of 15-45 µg/ml are achieved.

Nineteen healthy client-owned cats were enrolled in this study.  These patients all had no history of seizures or other neurologic disease, a normal neurologic examination, no other concurrent medication administration other than heartworm and/or flea prevention, and normal complete blood count, biochemical panel, and urine specific gravity > 1.030.

The cats were divided into three groups; all cats in the study were spayed or neutered.  Group 1 cats (n =6, all domestic shorthair cats) received transdermal phenobarbital in pluronic lecithin organogel (PLO) at 3 mg/kg q 12 hours for 14 days; this is a standard oral dosage for phenobarbital in cats.  Group 2 cats (n = 7, a mix of 4 domestic shorthairs, one domestic longhair, and one mixed breed Abyssinian) received their transdermal phenobarbital in PLO at 9 mg/kg q 12 hours for 14 days.  Group 3 cats (n =6, including 5 domestic shorthair and one domestic longhair) were treated with transdermal phenobarbital in the Lipoderm Activemax vehicle at 9 mg/kg q 12 hours for 14 days.  All owners completed a daily log of side effects and dosing times.  On day 15, serum phenobarbital levels were evaluated in all patients at trough levels, and 2, 4, and  6 hours after the morning dose.  Following this evaluation the prescribed dose of phenobarbital was given transdermally every 24 hours on days 15, 16, and 17 to avoid possible withdrawal side effects.  The phenobarbital treatments were then discontinued.

The mean serum concentrations of phenobarbital at steady state (Css) differed among the three groups.  In group 1, Css was < 15 µg/ml in all cats (dosage 3 mg/kg q 12 hours).  Group 2 cats had median serum phenobarbital concentrations at trough, and at 2, 4, and 6 hours for the six cats in this group that completed the study, of 26.0 µg/ml, 26.0 µg/ml, 25.5 µg/ml, and 25.5 µg/ml, respectively.  In all six cats in this group, serum phenobarbital concentrations never went below 18.0 µg/ml or exceeded 37.0 µg/ml at all time points tested.  In group 3 cats the serum phenobarbital concentrations were more variable than in Groups 1 and 2, who received the drug in the PLO vehicle. Group 3 serum phenobarbital concentrations varied from 5.0 µg/ml to 29.0 µg/ml at the various time points tested. In this group median serum phenobarbital concentrations at trough and at 2, 4, and 6 hours were 17.0 µg/ml, 15.5 µg/ml, 15.0 µg/ml, and 15.5 µg/ml, respectively, close to the low end of the recommended therapeutic serum concentration range.

There were mild adverse effects noted in some cats in group 1, including erythema of the inner surface of the ear pinna, ear grooming, mild increase in appetite,  mild increase in vomiting of trichobezoars, and mild polydipsia.  In group 2, 4/7 cats experienced adverse effects.  Most of these adverse effects, noted in one or two cats, were mild: paraparesis for 1-3 days, lethargy, trichobezoar vomiting, and ear grooming.  One of the 7 cats in this group was withdrawn from the study after day 3, having developed pelvic limb ataxia, polyphagia, sedation, and inappropriate mentation.  Five of the six group 3 cats also demonstrated adverse effects, among them polyphagia, polyuria/polydipsia, pelvic limb ataxia, mild lethargy, and increased ear grooming with medication crusting on the pinnae noted in each of one or two cats in this group.

The results of this study demonstrate that with chronic transdermal administration, therapeutic serum phenobarbital concentrations can be achieved in all or almost all cats using a dosage of 9 mg/kg in a PLO vehicle, and in some cats using the same dosage in Lipoderm Activemax.  Phenobarbital has almost complete oral bioavailability in cats, but transdermal bioavailability of this drug was hypothesized by these researchers to probably be lower than oral bioavailability, which is why a three-fold higher dosage for the transdermal preparation over the oral was utilized in this study.  Side effects in all patients receiving transdermal phenobarbital were minor and transient, and in general were limited to known side effects of oral phenobarbital, with the exception of pinnal erythema and increased ear grooming, which are known side effects of transdermal preparations applied to the ear.  Some of the cats were noted occasionally grooming their ears during the study, which could have led to some oral ingestion of the transdermal preparation.

One limitation in the use of the 9 mg/kg dosage of phenobarbital in PLO is the the relatively large volume of gel (0.22-0.44 ml/dose twice daily) that must be applied.  The dose had to be split between both pinnae at each dosing session, rather than alternating pinnae for each dose.  Attempts to increase the drug concentration in the PLO to > 125 mg/ml resulted in poor solubility of the drug.  Use of the Lipoderm Activemax vehicle allowed for a smaller volume of administration, but there was more variability in mean and median serum phenobarbital concentrations with the use of this vehicle.  Higher dosages of the drug in Lipoderm Activemax may be required for therapeutic serum levels to be achieved with this vehicle.  As with all phenobarbital preparations, monitoring of serum levels of this drug to assure that therapeutic concentrations are achieved is essential [PJS]

See also:
Pakozdy A, Sarchachi AA, et al.  Treatment and long-term follow-up of cats with suspected primary epilepsy.  J Feline Med Surg. 2013;15:267-73.

Smith BK, Dewey CW.  The seizuring cat. Diagnostic work-up and therapy.  J Feline Med Surg. 2009;11:385-94.