Loading…

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

Background and Aims 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 91 years. Methods An allometrically scaled pharmacokinetic m...

Full description

Saved in:
Bibliographic Details
Published in:Clinical pharmacokinetics 2018-08, Vol.57 (8), p.1039-1053
Main Authors: van Dijkman, Sven C., de Jager, Nico C. B., Rauwé, Willem M., Danhof, Meindert, Della Pasqua, Oscar
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background and Aims 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 91 years. Methods 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 (> 65 years), children (4–12 years) and infants and toddlers (0.2–2.0 years). 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. Results 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 4 years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7 years has a 31.5% higher CL, after correcting for body weight. Patients > 65 years of age showed a decrease in CL of approximately 15%. Conclusion 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. Trial Registration 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 ).
ISSN:0312-5963
1179-1926
DOI:10.1007/s40262-017-0614-5