Retrospective population pharmacokinetic analysis of seletracetam in epileptic and healthy adults
Marc-Antoine Fabre, Eliane Fuseau(1), Maria-Laura Sargentini-Maier, Nathalie Toublanc(2)
(1) EMF consulting, Aix-en-Provence, France ; (2) UCB S.A., Braine-l’Alleud, Belgium
Objectives: Characterization of population pharmacokinetics of the novel SV2A ligand seletracetam (ucb 44212) in healthy and epileptic adult populations to identify covariates that may have a clinically significant influence on its pharmacokinetics (PK) and simulation of the PK profiles in patients with the formulation planned for phase IIb-III studies.
Methods: 233 subjects received single or multiple twice daily doses of instant release formulation of seletracetam in 4 clinical pharmacology studies and 3 phase IIa studies. Seletracetam concentration-time data were analyzed using NONMEM. Food, age, gender, race, body weight (BW), body surface area, treatment duration, dose and concomitant antiepileptic drug (AED), health status and creatinine clearance were tested as possible covariates. Absorption parameters for once a day (o.d) formulation were derived under fasted and fed conditions from a pilot study. They were added to the final model to simulate the profiles after o.d administration, using demographic covariates of the phase IIa patients with appropriate replications.
Results: 194 subjects were Caucasians, 109 females, 24 elderly (above 65) and 124 epileptic subjects, with median (range) for BW and age of 74.5 (43-133) kg, and 36 (17-86) years. Seletracetam plasma concentrations were adequately described by a one-compartment model. BW, sex, age and enzyme inducing AEDs were identified as covariates affecting CL/F, resulting in a reduction of inter-individual variability (IIV) from 22% to 15%. The influence of the statistically significant covariates ranged between 16% (inducer AEDs) and 70 % (BW). BW and gender were also identified as covariates on V/F resulting in a reduction of IIV from 14% to 7%. The population mean of V/F was 0.6 and 0.5 L/kg for males and females. Food also had a significant effect on the absorption rate.Based on simulation of the o.d formulation in a population consisting of replication of phase IIa patients, in both fasted and fed conditions, Cmaxss, Cavss, and Cminss increased in females, by 27% to 43%. The influence of food on the o.d formulation was less than 15% on all parameters. The effect of inducing AEDs was relevant only on Cminss (decrease ca. 27%)..
Conclusions: Although some covariates were statistically significant, based on simulations of concentration vs. time profiles in patients of an o.d. formulation, the only ones that may have a relevant effect on exposure are BW, sex, and enzyme inducing AEDs.