Abstract
Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy.
Highlights
Due to its efficacy and safety profiles, levetiracetam is a second-generation antiepileptic drug currently arising as the most frequently prescribed for the prophylaxis and treatment of focal and generalized epilepsy [1,2]
The present investigation demonstrated that the pharmacokinetics of levetiracetam in Portuguese epileptic refractory patients is affected mainly by gender, body mass index, and co-administration of carbamazepine with consequences on drug exposure and plasma concentrations
To the best of our knowledge, this is the first study that assessed the pharmacokinetics of levetiracetam in a European population and the first including only refractory epileptic patients
Summary
Due to its efficacy and safety profiles, levetiracetam is a second-generation antiepileptic drug currently arising as the most frequently prescribed for the prophylaxis and treatment of focal and generalized epilepsy [1,2]. Several therapeutic targets have been ascribed for levetiracetam, it is clear that it modulates the synaptic vesicle glycoprotein 2A, with consequent reduction of the release of synaptic excitatory neurotransmitters, restoring the balance between inhibitory and excitatory synaptic activities [3,4,5,6,7] This unique mechanism of action may be linked with the usefulness of levetiracetam for the management of status epilepticus in pediatric and adult patients [8,9,10,11,12], prophylaxis of seizures from post-traumatic brain injury [13,14,15,16,17], neuropathic pain [18], and some psychiatric pathologies [19]. Levetiracetam crosses the blood–brain barrier quickly and, at steady state, brain concentrations are linearly related with those found in plasma [21,23]
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