Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials.

Abstract

In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91years. An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (>65years), children (4-12years) and infants and toddlers (0.2-2.0years). In addition, simulations were performed to identify the implication of different doses and dosing regimens for each population, so as to ensure steady-state concentrations within a predefined reference range. The pharmacokinetics of lamotrigine was best described using a one-compartment model with first-order absorption and elimination. Carbamazepine, phenytoin, and valproic acid changed systemic clearance (CL) by +76.5, +129, and -47.4%, respectively. Allometric principles allowed accurate extrapolation of disposition parameters to older adults and children older than 4years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7years has a 31.5% higher CL, after correcting for body weight. Patients>65years of age showed a decrease in CL of approximately 15%. Population pharmacokinetic models are usually limited to a subgroup of patients, which may mask the identification of factors contributing to interindividual variability. The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials. According to GlaxoSmithKline's Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b , https://doi.org/10.1111/j.1528-1167.2007.01274.x ).