Abstracts

Rationale: To characterize the population pharmacokinetics of a new once daily extended-release formulation of levetiracetam (LEV XR) administered as 500 mg tablets in healthy subjects and in epilepsy patients with partial-onset seizures, to identify factors affecting pharmacokinetic parameters, and to simulate scenarios of non-compliance and the exposure comparing 1000 mg of LEV XR once daily to 500 mg twice daily of the immediate-release levetiracetam (LEV IR). Methods: Data consisted of concentration-time profiles following single-dose (fed and fasted) and multiple-dose administration of (i) LEV XR or LEV IR tablets in healthy volunteers and of (ii) LEV XR tablets in epileptic patients with partial-onset seizures. In total, 3648 plasma concentration measurements were available from 48 healthy subjects and 73 subjects with epilepsy. LEV plasma concentration-time data were modeled by non-linear effects modeling using NONMEM VI. The structural model was a one-compartment pharmacokinetic model, with first-order elimination and first-order absorption and lag-time. The model was parameterized in terms of apparent distribution volume (V/F), clearance (CL/F), absorption rate constant (Ka), and lag-time (ALAG1). An additive and proportional combined error model was used. Results: All the structural parameters of the final model were estimated with good precision. The typical first order absorption rate constant was about 20-fold lower for LEV XR tablet than for IR tablet and was only slightly reduced by a high fat meal. As expected, the corresponding absorption half-times (ln(2)/Ka) were 0.1 h, 2 h and 2.3 h for levetiracetam IR, XR fasting, and XR fed, respectively. For the typical individual, LEV XR shows an apparent clearance and distribution volume of 0.95 mL/min/kg and 0.6 L/kg respectively, which are consistent with previous knowledge of oral LEV IR pharmacokinetics. Bodyweight affected CL/F and V/F by [-20%; +50%] and [-10%; +20%] around the typical value, respectively, over the extreme weights of 50 kg and 120 kg. Clearance was approximately 15% lower in females and was modified by about 10% over the range of creatinine clearances. Deviations from the planned dosing schedule were simulated for scenarios of missing dose, dose taken late, missing dose followed by double rescue dose the day after. The model predicts that the return to the initial peak and trough conditions takes place within 24 hours. Simulations performed on a typical individual taking LEV IR bid or LEV XR once daily confirmed the exposure equivalence between the two formulations. Conclusions: Patients taking levetiracetam extended-release 2x500 mg once daily, appeared to be adequately exposed to levetiracetam with predicted concentrations in the range of those observed after levetiracetam immediate-release 500 mg twice daily dosing. Study sponsored by UCB.