Toublanc N, Lacroix BD
Pharmacometrics, Global Exploratory Development, UCB Pharma SA, Belgium
Objectives: This population pharmacokinetic (PK) analysis aimed i) to assess the PK of levetiracetam (LEV) in Japanese children and adults, ii) to assess dose recommendations in Japanese children to support the pediatric submission in Japan and iii) to compare the PK of LEV in the Japanese and Caucasian population.
Methods: The population PK analysis was performed using NONMEM based on plasma LEV concentrations from Japanese children and adult with partial-onset seizures who received adjunctive LEV BID during more than10 weeks in 3 studies. The doses administered as dry syrup or tablet were 10mg/kg bid to 30mg/kg bid for the children, capped to the adult dose of 500mg bid to 1500mg bid. Bodyweight (BW) was included in the base model on clearance (CL/F) and distribution volume (V/F). Age, formulation and concomitant anti-epileptic drugs (AEDs) were examined as possible covariates to explain inter-individual variability in pharmacokinetic parameters of LEV. The model was used to simulate and compare concentrations in Japanese children and adults following various dosing regimens with the 2 formulations. The similarity of the PK in Caucasian and Japanese children was assessed through external validation.
Results: 1840 concentration-time records were available from 259 Japanese subjects (73 children and 186 adults). LEV plasma concentrations were adequately described by a one-compartment model, with low residual variability (20.0% CV). Only concomitant enzyme inducing AEDs was a significant covariate on CL/F, in addition to BW with allometric exponents on CL/F and V/F. Simulations of the dosing regimens expected in clinical practice for Japanese children lead to similar concentrations as those simulated in Japanese adult with the currently recommended regimen. The model developed in Japanese subjects with no modification gave a good prediction of the concentrations obtained in Caucasian children (historical data).
Conclusions: i) The population PK model gave a good description of the PK of LEV both in Japanese children and adults. ii) The appropriateness of the dosing regimens expected in clinical practice for Japanese children to reach concentrations in the ranges of those predicted in Japanese adults was confirmed. iii) The PK between Japanese and Caucasian children was similar.
Reference: PAGE 21 (2012) Abstr 2405 [www.page-meeting.org/?abstract=2405]
Poster: Paediatrics