Abstracts

Rationale: Lamictal XR® is an enteric-coated tablet with an extended-release core. A study was designed to evaluate the absolute bioavailability of lamotrigine (LTG) in the XR and standard formulation in elderly patients on maintenance therapy. Lamotrigine is better tolerated in elderly patients than carbamazepine and a once daily formulation would improve compliance in this population. Methods: This study is designed to enroll 12 subjects, 65 years or older being treated with LTG for epilepsy. The intravenous form of LTG was developed by our group and labelled with 13C and 15N. A tracer-dose of stable-labelled LTG, 13C2,15N-LTG, 50 mg, was administered intravenously to patients at steady-state on both formulations in a crossover design. Patients were switched to Lamictal XR® from Lamictal® for at least one week prior to the second IV dose of 13C2,15N-LTG. LTG and 13C2,15N-LTG concentrations (14 samples/patient) were determined by a GC-MS assay (C.V. ≤ 15%). Pharmacokinetic analyses to calculate AUC and F were done by non-compartmental analysis with WinNonlin. Results: At the time of submission, six patients have completed the study. GC-MS analysis for unlabelled drug has been done for one patient. The relative bioavailability (calculated from 24 hr AUCs) determined from unlabelled LTG concentrations was 81.5% for LTG-XR in this patient. Conclusions: Simultaneous use of intravenous stable isotope technology in relative bioavailability studies is an elegant method to simultaneously determine absolute bioavailability and other pharmacokinetic parameters in patients on maintenance therapy. The method overcomes changes in GI physiology in elderly patients that can influence the absorption of sustained release products that are often only tested in younger healthy volunteers. Supported by a investigator-initiated grant from Glaxo SK and NIH P50 NS16308.