Page 3 - Levetiracetam (Keppra®)

Gabapentin is similar to Keppra® in terms of half-life and impact on dosing and steady-state. Accordingly, we suggest
using Keppra recommendations for sample collection. The therapeutic range in humans of 12 to 21 mcg/ml may or may not be
relevant in animals. We are concerned the oral bioavailability of gabapentin is variable in dogs and accordingly recommend
monitoring in animals receiving gabapentin for seizure control.

Phenobarbital is characterized by a half-life of approximately 54-72 hrs in dogs and similar in cats; variability among
animals is likely to be marked. We have measured a half-life as short as 12 hrs; for such patients, steady-state does not really
occur. As such, during a 12 hr dosing interval, because little drug is eliminated between doses, drug concentrations will
accumulated. “Steady-state” should occur in 3 to 5 drug half-lives, or 150 to 360 hrs (approximately 2 weeks).

The therapeutic range recommended in animals is 15 to 40 mcg/ml, although we recommend that
concentrations remain below 35 mcg/ml, and ideally, less than 25 mcg/ml to reduce the risk of hepatotoxicity.

When: Baseline steady-state concentrations can be determined at 14 days. Because Phenobarbital can induce
drug metabolism, we recommend another sample at 3 months, particularly for patients whose history includes severe
seizures.
Sampling times: For routine monitoring, either a peak (2 hr) or trough (just before the next dose) is reasonable,
although we suggest a trough sample such that the lowest concentrations can be determined for the patient and so that
concentrations can be compared across time. Also, in some patients, the half-life is short enough that trough
concentrations are significantly lower than peak. Peak and trough samples are necessary only for animals in which a half-
life less than 20 hrs is suspected such that a shorter dosing interval might be recommended. This might occur in a patient
whose liver has been induced to more rapidly metabolize the drug. Remember that any time the dose is changed, you
should monitor again at 2 to 4 weeks.

Other considerations: Phenobarbital will shorten the half-life of other drugs, including levetiracetam and zonisamide.
Its half-life will be prolonged or shorted by other drugs that target drug metabolizing enzymes. Drugs known to have decrease
phenobarbital in our lab have included chloramphenicol and imidazole antifungals.

Zonisamide (Zonegran®) is characterized by a half-life of approximately 20-40 hrs in dogs (unknown in the cat)
variability among animals is likely to be marked. As such, during a 24 hr dosing interval, drug concentrations will decline by
approximately 50%. We recommend, therefore, that a 12 hr dosing interval be implemented to avoid inappropriate fluctuation
during the dosing interval. “Steady-state” should occur in 3 to 5 drug half-lives, or 60 to 100 hrs (3 to 5 days). However, we have
commonly measured half-lives longer than 150 hrs, suggesting that drug metabolism in dogs might “saturate” (the drug is
acetylated, which is an enzyme in which the dog is deficient). As such zonisamide recommendations are very similar to
phenobarbital in terms of when and what.

The therapeutic range recommended in animals is currently that recommended in humans, that is, 10 to 40
mcg/ml. Assuming that this therapeutic range is appropriate for dogs or cats, we suggest that doses be designed to achieve
a “low” concentration of 15 to 20 mcg/ml as therapy is begun. We have measured (often) concentrations well above 60
mcg/ml or higher; dogs appear to tolerate this concentration well, although safety has not been confirmed.

When: Baseline steady-state concentrations can be determined at 7 to 14 days. Steady-state will thus take longer
than 10 to 14 days in those patients. The half-life is likely to be shorter in dogs simultaneously receiving Phenobarbital;
up to a 30% decrease in half-life or drug concentrations may occur. However, this is not consistent.

Sampling times: For routine monitoring, either a peak (2 hr) or trough (just before the next dose) is reasonable,
although we suggest a trough sample such that the lowest concentrations can be determined for the patient and so that
concentrations can be compared across time. Peak and trough samples are necessary only for animals in which a half-life
less than 20 hrs is suspected such that a shorter dosing interval might be recommended. However, for some patients, a
peak and trough might be prudent to detect longer half-lives that might lead to marked drug accumulation.

Other considerations: We are concerned that the oral bioavailability of zonisamide varies among the generic human
products, meaning that one product may be absorbed differently than another product in the same dog. Accordingly, clients may
want to ask the pharmacist to let them know when the pharmacy has changed the manufacturer of the generic product; monitoring
might be implemented after the change has been made in the patient.

Thyroid gland suppression may be more likely at this concentration. Baseline thyroid function testing is recommended as
you begin zonisamide and repeated as concentrations reach the maximum.

Phenobarbital will substantively decrease the half-life of zonisamide. If phenobarbital is discontinued in an animal, note
that zonisamide concentrations will likely increase.

IMMUNOMODULATORY DRUGS