A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria

Gretchen L Birbeck, Susan T Herman, Edmund V Capparelli, Fraction K Dzinjalamala, Samah G Abdel Baki, Macpherson Mallewa, Neema M Toto, Douglas G Postels, Joseph C Gardiner, Terrie E Taylor, Karl B Seydel, Gretchen L Birbeck, Susan T Herman, Edmund V Capparelli, Fraction K Dzinjalamala, Samah G Abdel Baki, Macpherson Mallewa, Neema M Toto, Douglas G Postels, Joseph C Gardiner, Terrie E Taylor, Karl B Seydel

Abstract

Background: Acute seizures are common in pediatric cerebral malaria (CM), but usual care with phenobarbital risks respiratory suppression. We undertook studies of enteral levetiracetam (eLVT) to evaluate pharmacokinetics (PK), safety and efficacy including an open-label, randomized controlled trial (RCT) comparing eLVT to phenobarbital.

Methods: Children 24-83 months old with CM were enrolled in an eLVT dose-finding study starting with standard dose (40 mg/kg load, then 30 mg/kg Q12 hours) titrated upward until seizure freedom was attained in 75% of subjects. The RCT that followed randomized children to eLVT vs. phenobarbital for acute seizures and compared the groups on minutes with seizures based upon continuous electroencephalogram. Due to safety concerns, midway through the study children allocated to phenobarbital received the drug only if they continued to have seizures (either clinically or electrographically) after benzodiazepine treatment. Secondary outcomes were treatment failure requiring cross over, coma duration and neurologic sequelae at discharge. PK and safety assessments were also undertaken.

Results: Among 30 comatose CM children, eLVT was rapidly absorbed and well-tolerated. eLVT clearance was lower in patients with higher admission serum creatinine (SCr), but overall PK parameters were similar to prior pediatric PK studies. Within 4 h of the first dose, 90% reached therapeutic levels (> 20 μg/mL) and all were above 6 μg/mL. 7/7 children achieved seizure freedom on the initial eLVT dose. Comparing 23 eLVT to 21 phenobarbital patients among whom 15/21 received phenobarbital, no differences were seen for minutes with seizure, seizure freedom, coma duration, neurologic sequelae or death, but eLVT was safer (p = 0.019). Phenobarbital was discontinued in 3/15 due to respiratory side effects.

Conclusion: Enteral LVT offers an affordable option for seizure control in pediatric CM and is safer than phenobarbital.

Trial registration: NCT01660672 . NCT01982812 .

Keywords: Acute symptomatic seizures; Tropics.

Conflict of interest statement

The authors have no conflicts of interest relevant to this article to disclose.

Figures

Fig. 1
Fig. 1
Measured relative to predicted levetiracetam concentrations among children with cerebral malaria receiving enteral LVT stratified by admission serum creatinine. LVT = levetiracetam. SCr = serum creatinine
Fig. 2
Fig. 2
The frequency of observed levetiracetam concentrations 4 h after the first dose and predicted steady-state troughs and average concentrations. All 4 h post first dose and average steady state levels were above 6 μg/mL. LVT = levetiracetam
Fig. 3
Fig. 3
Levetiracetam clearance, levels and half-live in relation to admission serum creatinine. LVT = levetiracetam. SCr = serum creatinine
Fig. 4
Fig. 4
Randomized Control Trial Profile. * “Usual Care” group initially received phenobarbital at enrollment, but protocol revised in 2015 such that “Usual Care” group only received phenobarbital if seizures recurred after allocation

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