Abstracts

Rationale: The primary treatment objectives for patients with epilepsy are maintenance of relatively stable and effective antiepileptic drug (AED) levels and prevention of subsequent seizures. Compliance with the prescribed dosage regimen is essential for the maintenance of therapeutic blood levels. An extended release formulation of lamotrigine (LTG) has been developed (LTG-XR) which slows the dissolution rate of LTG over a period of approximately 12-15 hours with a modified release eroding matrix formulation. This abstract provides an overview of the pharmacokinetic properties of this formulation in healthy volunteers and patients with epilepsy.Methods: A series of clinical pharmacology studies have been conducted in healthy volunteers and patients with epilepsy to investigate: 1) The effect of food on the pharmacokinetics of LTG-XR, 2) Dose proportionality of LTG-XR from 25 to 200 mg, 3) Dosage strength equivalence of administering 2 LTG-XR tablets versus a single LTG-XR tablet, and 4) Steady-state relative bioavailability of LTG-XR compared to LTG immediate release (LTG-IR).Results: The administration of LTG-XR with a high fat breakfast did not affect the pharmacokinetics of LTG in 46 healthy volunteers. Systemic exposure was dose-proportional between 50 and 200mg of LTG-XR in 18 healthy volunteers. Doses between 25 mg and 50mg were less than dose proportional. For the 2-fold increase in dose there was an approximate 1.6 fold increase in exposure, this observation is not considered to be clinically relevant as this meets the defined bioequivalent margin of 80% of the desired dose. Administration of a same dose administered as 2 tablets vs a single tablet did not affect the PK profile of LTG. Steady-state relative bioavailability was assessed in 44 patients with epilepsy. Exposure (AUC) and trough concentrations were similar following LTG-XR compared to LTG-IR given at the same total daily dose. A dose-normalized assessment of the relative bioavailability of LTG at steady state (LTG-XR vs LTG-IR) was performed and is summarized in the table below. Patients were assigned to a group based on their concurrent antiepileptic drugs (AED) (induced, inhibited and neutral AEDs).Conclusions: LTG-XR can be administered without regard to food since the controlled release characteristics of LTG-XR do not appear to be affected by high-fat meals. The overall systemic exposure and trough concentrations of lamotrigine are similar between LTG-XR and LTG IR in patients with epilepsy. This supports the proposed dosing of LTG-XR as the same as LTG-IR for escalation and maintenance of therapy for patients with epilepsy.