Pharmacokinetic and Pharmacodynamic Evaluation of Intravenous Levetiracetam in Children with Epilepsy
Min-Jee Kim1, Mi-Sun Yum1, Hye-Ryun Yeh1, Tae-Sung Ko1, Hyeong-Seok Lim2
1Department of Pediatrics, Asan Medical Center Children’s Hospital, Seoul, Korea
Objectives: This study aimed to evaluate the safety and tolerability of intravenous (IV) levetiracetam (LEV) as monotherapy in children aged 1 month to 16 years old and further to explore the pharmacokinetics (PK) of IV LEV and the time to seizure after IV and then oral administration of LEV in pediatric patient with epilepsy.
Methods: An open-label, single-arm, single centersingle-center trial for pediatric patients with epilepsy was conducted to evaluate the PK, frequency of seizure recurrence, and toxicity of IV LEV. Children diagnosed with any type of acute unprovoked seizure and requiring in-hospital IV LEV administration were included. Plasma LEV (m/z 171.0) concentrations were measured using high-performance liquid chromatography with tandem mass spectrometry after sample preparation by liquid-liquid extraction. Clinical seizure outcomes, side effects, and Korea-child behavior checklist after administration were monitored and the PK, repeated time to seizure was analyzed via modeling using NONMEM in these children. A total of 107 plasma concentrations of LEV from 37 children (median age, 4.6 years; median weight, 18.0 kg) with epilepsy who received IV LEV were used for the current PK analysis. Seizure recurrence data were collected retrospectively from a total of 34 pediatric patients in Asan Medical Center who received a single IV and then multiple oral doses of LEV during the study.
Results: The plasma LEV concentrations after IV LEV were best described by one-compartment linear PK model. Only body weight was associated with both clearance (CL) and volume of distribution (V) of LEV in the power model. Typical CL and V in children of 18 kg in body weight were, 1.44 L/h and 8.55 L, respectively. Basic goodness of fit plots and model predicted vs. observed LEV concentration plots indicated that the final PK model is reasonable. The body weight proved statistically significant in randomization tests since the minimum objective function value (MOFV) of the final PK model was a lot lower than the 2.5th percentile of the MOFV distribution obtained from 1,000 datasets where the WT was randomly permuted. Weibull distribution model described the time to seizure recurrence well with estimates for scale and shape parameters of 0.01 and 0.77, respectively. In the covariate analysis, no statistically significant predictor for the time to seizure recurrence was identified. The model prediction was in good agreement with the Kaplan–Meier curve.
Conclusions: This study evaluated the PK, treatment effect and adverse events after a single IV LEV and repeated time to seizure recurrence after a single IV LEV followed by multiple oral doses of LEV in children with acute repetitive seizures or status epilepticus. The PK modeling analysis identified body weight as a covariate affecting the PK of IV LEV in children. The repeated time to event modeling analysis described the seizure recurrence over time after conventional LEV therapy in children. The current study results provide practical knowledge that applies to optimal, individualized LEV therapies in children with epilepsy.
References:
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