Page 2 - Levetiracetam (Keppra®)

will accumulate until a steady-state is reached. Because of this long half-life, the sampling time for bromide can be any time
during a dosing interval. Monitoring should occur at:
Baseline: “Steady-state” should occur in 3 to 5 drug half-lives, or 2.5 to 3 months after dosing at the same dosing
regimen. Baseline steady-state concentrations can be determined only at that time. To pro-actively assess the appropriateness of
your dose, (for example, patients at risk for therapeutic failure), we recommend that you check concentrations half-way to steady-
state, that is, at one half-life (2 to 3 weeks). This concentration can be doubled to predict steady-state concentrations. A steady-
state sample should be collected at 3 months to confirm baseline concentrations.
Loading: If the patient is loaded, in the “at risk” patient, we suggest that a sample be collected the day after the loading
dose is administered to determine “what was accomplished” with loading and again 2 to 3 weeks later, to test the accuracy of the
maintenance dose, and finally at 2.5 to 3 months to establish baseline. Alternatively 2 -3 months into maintenance dosing.
Rationale: While concentrations achieved once a loading dose is completed may be in the therapeutic range, the patient is
NOT at steady-state and will not be until it has been dosed with the maintenance dose for 2.5 to 3 months. If the maintenance
dose does not maintain what you accomplished with the loading dose, serum bromide concentrations will slowly decline or
increase, depending on how incorrect the maintenance dose is. (or increase, which is often not problematic), until steady-state is
reached. The patient may start seizuring again at 3 to 4 weeks post load if the maintenance dose is too low, or become groggy if it
is too high. A sample collected at 2 to 3 weeks into the maintenance dose (after loading is completed) will assure that the
maintenance dose is “maintaining” what you achieved with loading. If you collect a 2-3 week sample without also collecting the
post-load sample, we will not be able to tell if serum bromide concentrations have changed compared to the loading concentration.
Other considerations: Consider monitoring in advance of a drastic change in the preparation being given (ie, chew tablet
to solution, change in pharmacy, etc). Remember that bromide will cause serum chloride concentrations to appear deranged due to
interference with the chloride assay.

Levetiracetam (Keppra®) is characterized by a half-life of 2 to 4 hrs in dogs (regular release) and 4 to 7 hrs in cats;
variability among animals is likely to be marked. For extended release, the half-live may be 1-2 hrs longer. As such, if the dosing
interval is 8 hr most, if not all of each dose will be eliminated during a dosing interval in dogs and 50% to 75% of the dose will be
eliminated in cats. For extended release, with a 12 hr dosing interval, the same may be true.“Steady-state” never truly occurs for
levetiracetam in dogs (and may not in cats) because the drug does not accumulate with each dose.

The therapeutic range recommended in dogs or cats currently is that recommended in humans which is a trough
concentration of that is 5 to 45 mcg/ml, depending on the resource.

When: Because minimal accumulation occurs, concentrations can be measured within days to 1 week of initiating a new
dosing regimen.

Sampling times:
We suggest that dosing regimens be designed based on both a peak and trough as drug therapy is initiated.
A single sample collected before trough cannot predict drug concentrations throughout the dosing interval. For
example, assuming a peak concentration of 50 mcg/ml is achieved, and a 2 hr half-life, this means that three elimination
half-lives will lapse before the next dose. Concentrations will be subtherapeutic before the next dose: 50 to 25 to 12.5 to
6.125 mcg/ml. It is important to know your patient’s half-life. This will allow you as clinician to assess how short the
half-life is and in turn, warn the client about the magnitude of fluctuation in drug concentrations during the dosing
interval and the risk of drug concentrations dropping below the therapeutic range. Once a half-life has been calculated for
your patient, an appropriate dosing interval can be designed. The peak sample should be taken at 2 to 3 hrs and the trough
just before the next dose unless otherwise directed based on previous monitoring that indicated the half-life was too short
for drug to be detected at 8 or 12 hrs.

If only a single sample can be collected, it should be a trough sample. Note that if you collect a sample at 12
hrs, with an 8 hr dosing interval, the trough measurement may markedly underestimate the true trough concentration.
For recommendations, it is critical that the timing of sample collection be provided on the submission form.

In the case of therapeutic failure, we do not suggest that the sample only be collected at the same time during a
dosing interval that the seizure occurred, but that a trough sample be collected as well such that half-life can be
calculated.

Other considerations:

A slow release levetiracetam (Keppra®) product is available for use in humans; our preliminary data suggests
the half-life will be longer in dogs, allowing (potentially) a 12 dosing interval. However, monitoring both a peak and
trough will be important to establishing the correct dosing interval in dogs or cats when using the slow release product.
Note that the compounded slow release product that is designed for humans is not likely to demonstrate slow release
kinetics in the dog (or cat). Monitoring should be done to demonstrate its efficacy.

Phenobarbital will decrease levetiracetam half-life.

Levitiracetam is metabolized largely by plasma enzymes. Metabolism will continue in situ in plasma. As such, serum
samples should be collected to avoid falsely lower than actual concentrations.