Population pharmacokinetics of the new antiepileptic drug lacosamide in healthy subjects with different age and gender
Brunhild Schiltmeyer, Willi Cawello, Dirk Kropeit, Rolf Horstmann
Clinical Development, SCHWARZ BIOSCIENCES GmbH, Monheim, Germany
Objectives: Characterization of population pharmacokinetics of the new antiepileptic drug lacosamide in young healthy male and elderly healthy male and female subjects in order to identify possible covariates that may have an influence on the pharmacokinetics (PK) of lacosamide.
Methods: 47 subjects received a single dose of 100 mg lacosamide or placebo on day 1 and day 8 and a multiple dose of 100 mg lacosamide bid or placebo on day 4 to day 7 in a single-center, double-blind, parallel group trial. Blood sampling was done after single dose on day 1 and after multiple doses following the last dose on day 8. Lacosamide concentration-time data were analyzed using nonlinear mixed-effect modeling (NONMEM). The parameters age, gender, body weight, height, and creatinine clearance (CLcrea) were tested as possible covariates to explain inter-individual variability in PK parameters of lacosamide.
Results: Lacosamide plasma concentrations were adequately described by a 1 -compartment model with low residual variability (<10%, combined residual error model). Height and gender were identified as covariates on V/f resulting in a reduction of inter-individual variability of V/f from 21% to 10%. The population mean of V/f was estimated to be 42.4 L for a male subject with a median height of 1.69 m and 35.5 L (=16% decrease) for a female subject with the same height, respectively. Additionally, CLcrea and gender were identified as covariates on ke resulting in a reduction of inter-individual variability of ke from 19% to 15%.The population mean of ke for a subject with a median value of CLcrea of 89 mL/min was estimated to be 0.044 h-1 (t1/2 of 15.8 h) for males and 0.051 h -1 (t1/2 of 13.6 h) for females (=14% decrease), respectively.
Conclusions: An appropriate population PK model was successfully developed to characterize plasma concentration-time data of lacosamide after oral administration. Based on the results, the influence of the tested covariates on the PK of lacosamide could be described and quantified within the trial population of healthy subjects. A major part of the variability of V/f can be explained by differences in height and gender. The observed higher plasma concentrations of lacosamide in females were the result of the smaller V/f in this subpopulation. Additionally, as lacosamide is highly soluble in water and mainly distributes in extracellular fluid, changes in height are linked with changes in V/f. In summary, lacosamide was found to be a particularly suitable drug for population PK. As the inter-individual variability of V/f and ke can be explained to a large extent and the identified covariates only have a minor influence on PK parameters, lacosamide is an antiepileptic drug with a highly predictable exposure in individual subjects.
The current model is capable of being used as basis for population PK evaluations in Phase 2/3 to verify the current results in the target patient population.