Oral absorption of levetiracetam is rapid and nearly complete, with peak plasma concentrations in 1.3 hours. Food slows the rate of absorption but does not affect the amount absorbed. Kinetics are linear. Protein binding is less than 10%. The plasma half-life is 6–8 hours, but may be longer in the elderly. Two-thirds of the drug is excreted unchanged in the urine and the remainder as the inactive deaminated metabolite 2-pyrrolidone-N-butyric acid. The metabolism of levetiracetam occurs in the blood. There is no metabolism in the liver, and drug interactions are minimal.
Brivaracetam, the 4-n-propyl analog of levetiracetam, is a high-affinity SV2A ligand recently approved for the treatment of focal (partial) onset seizures. Whether it will prove to have the broad-spectrum activity of levetiracetam remains to be demonstrated; given the similarity of the mechanisms of action, however, a broad spectrum is expected. Brivaracetam is active in animal models of generalized epilepsies. It improved or abolished the photoparoxysmal response (abnormal occurrence of cortical spikes or spike and wave discharges on EEG in response to intermittent light stimulation) in patients with generalized epilepsies. In addition, the drug reduced the frequency of generalized seizures in a small number of patients with generalized seizures included in a clinical trial. Brivaracetam exhibits linear pharmacokinetics over a wide dose range (10–600 mg, single oral dose). It is rapidly and completely absorbed after oral administration; has an elimination half-life of 7–8 hours, which allows twice-daily dosing; and has low plasma protein binding (<20%).
Coadministration of brivaracetam with carbamazepine may increase exposure to carbamazepine epoxide, the active metabolite of carbamazepine, possibly leading to adverse effects; carbamazepine dose reduction should be considered. Similarly, coadministration of brivaracetam with phenytoin may increase phenytoin levels. Coadministration of other antiseizure drugs is unlikely to affect brivaracetam exposure. Brivaracetam provides no added therapeutic benefit when administered in conjunction with levetiracetam; both drugs act on SV2A.
Perampanel is an orally active AMPA receptor antagonist approved for the treatment of focal seizures and primary generalized tonicclonic seizures in idiopathic generalized epilepsies.
Mechanism of Action
Perampanel is a potent noncompetitive antagonist of the AMPA receptor, a subtype of the ionotropic glutamate receptor that is the main mediator of synaptic excitation in the central nervous system (Figure 24–1). AMPA receptors are critical to local generation of seizure activity in epileptic foci and are also responsible for the neuron-to-neuron spread of excitation. Partial blockade of AMPA receptors by therapeutic concentrations of perampanel reduces the likelihood of seizure occurrence. In generalized convulsive seizures, whether occurring as a secondarily generalized convulsion following a focal seizure or as a primary generalized seizure, excitatory cortical neurons engage subcortical centers, including the thalamus, that relay the excitation throughout both hemispheres. This spread of excitation to distant sites is mediated by AMPA receptors at the excitatory synapses that long axons make on their distant targets. Perampanel is therefore well suited to inhibit this spread of excitation, which may account for its activity in preventing secondary and primary generalized convulsive seizures. Perampanel binds to an allosteric site on the extracellular side of the channel, acting as a wedge to prevent channel opening.