Lamotrigine pharmacokinetics following oral and stable‐labeled intravenous administration in young and elderly adult epilepsy patients: Effect of age

• Published in: Epilepsia (Copenhagen) 2018-09, Vol.59 (9), p.1718-1726
• Main Authors: Polepally, Akshanth R., Brundage, Richard C., Remmel, Rory P., Leppik, Ilo E., Pennell, Page B., White, James R., Ramsay, R. Eugene, Kistner, Brett M., Birnbaum, Angela K.
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Adolescent; Adult; Age; Aged; Aged, 80 and over; Anticonvulsants - administration & dosage; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; antiseizure drug; Bioavailability; Body weight; Coronary artery disease; Data processing; elderly; Epilepsy; Epilepsy - drug therapy; Female; Gas chromatography; Geriatrics; Heart diseases; Humans; Intravenous administration; Lamotrigine; Lamotrigine - administration & dosage; Lamotrigine - blood; Lamotrigine - pharmacokinetics; Liver diseases; Male; Mass spectroscopy; Middle Aged; Models, Statistical; Patients; Pharmacokinetics; Time Factors; Young Adult
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.14519

Summary Objective The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability. Methods Patients (>18 years old) who were already on a steady‐state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate‐to‐severe liver dysfunction were excluded. Fifty milligrams of a stable‐labeled intravenous LTG formulation (SL‐LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL‐LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography–mass spectrometry. Concentration‐time data were analyzed by nonlinear mixed‐effects modeling (NONMEM version 7.3). Results Twenty‐eight patients representing 16 young (18‐48 years old) and 12 elderly (63‐87 years old) patients were included, yielding 382 unlabeled and 351 SL‐LTG concentrations. A two‐compartment model with first‐order absorption and elimination adequately described the plasma concentration‐time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70‐kg patient). Significance Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.