Julia Winkler (1), Rik Schoemaker (2), Armel Stockis (3)
(1) SGS Exprimo, Mechelen, Belgium, (2) Occams, Amstelveen, The Netherlands, (3) UCB Pharma, Braine l’Alleud, Belgium
Objectives: To predict the intravenous (IV) PK profile of lacosamide (LCM) in children, by combining the healthy adult IV and oral PK characteristics from two bioavailability studies with the pediatric oral PK characteristics obtained from a recently developed population PK model, to simulate different dosing regimens of IV infusions of LCM in pediatric subjects with epilepsy, and to propose dose adaption rules.
Methods: A population PK model was developed for LCM using a combined dataset of healthy adult subjects with IV and oral dosing and pediatric subjects with epilepsy with oral dosing (using NONMEM v.7.2.0 with FOCEI). A structural model with zero and first order absorption after oral administration, two compartment distribution, and first order elimination described the data well. Plasma clearance was modelled using allometric scaling on body weight with a fixed theoretical allometric exponent, and volume of distribution with a freely estimated allometric exponent. Residual error was modeled using separate proportional error terms for the adult and pediatric population. In addition, co-administration of enzyme-inducing drugs was included as a covariate on clearance.
The final model was used to predict different LCM IV dosing regimens with varying duration (15-60 min) in pediatric subjects with epilepsy and to propose dose adaption rules.
Results: LCM plasma concentration-time data were available from 43 intensely sampled healthy adult subjects (n=1735), and from 72 sparsely sampled and 7 intensely sampled children (body weight 6–76 kg) (n=402), with 9, 26, 23, and 21 patients in age groups 0 to <2 years, 2 to <6 years, 6 to <12 years, and 12 to <18 years, respectively.
Median steady state peak plasma concentrations (Cmax) at the end of a 15-min IV infusion were predicted to be 9-21% higher compared to median Cmax values after oral administration; this decreased to 2-10% after a 60-min IV infusion. Exposure was fairly similar between both routes of administration and independent of infusion duration supporting the interchangeability of oral and IV dosing approved in adults.
Conclusions: The model adequately described LCM plasma concentrations in healthy adults and children with epilepsy. Model‑based PK predictions suggest that there is no need to adapt the recommendations regarding IV infusion durations in children compared to adults using weight-based dosing with or without loading doses aiming to reach exposures in the same range as in adults.
Reference: PAGE 25 (2016) Abstr 6034 [www.page-meeting.org/?abstract=6034]
Poster: Drug/Disease modeling - Paediatrics