Rik Schoemaker (1) and Armel Stockis (2)
(1) Exprimo, Mechelen, Belgium, and (2) UCB Pharma, Braine-l’Alleud, Belgium
Objectives: To develop a PK/PD model of spontaneously reported adverse events (AE) with the antiepileptic drug lacosamide and to apply it to predicting the changes in time profile and incidence of adverse events following switch from a conventional immediate release (IR) tablet to a modified release (MR) formulation.
Methods: PK and AE data were obtained from a double blind placebo-controlled steady-state parallel group Thorough QT study involving 193 healthy volunteers. PK data from a pilot bioavailability study with single dose MR formulations were also included. Plasma concentrations were fitted to a pharmacokinetic model using non-linear mixed-effects modelling implemented in NONMEM V7.2.0. AE data consisted of the five most frequent spontaneously reported AEs: nausea, vomiting, dizziness, oral hypoaesthesia and headache. Each AE was modelled using non-linear mixed-effects modelling (Laplacian method) with a proportional odds model for ordered categorical data with a Markov element[1] accounting for the correlation between successive scores, a linear concentration effect relationship, and a component describing AE incidence reduction over time.
Results: A one-compartment model with first-order absorption, diurnal effect on clearance and combined (multiplicative + additive) error was shown to adequately describe lacosamide pharmacokinetics. The final PK model allowed simulation of the once-daily multiple administration of the MR formulation in comparison with twice-daily administration of the IR form. Simulations suggest that these two administration modes cover a similar concentration range with lower peaks for the MR formulation and predict a modest reduction in incidence of adverse events for the MR formulation compared with the IR formulation at the same total daily dose.
Conclusions: Modelling and simulation of lacosamide pharmacokinetics and of the spontaneously reported AEs suggest that slowing down the absorption rate can possibly result in improved tolerability.
Reference:
[1] Zingmark PH, Kågedal M, Karlsson MO. Modelling a spontaneously reported side effect by use of a Markov mixed-effects model. J Pharmacokin Pharmacodyn (2005) 32(2): 261-81.
Reference: PAGE 21 (2012) Abstr 2380 [www.page-meeting.org/?abstract=2380]
Poster: CNS