The Loss-of-Function ATP Binding Cassette Subfamily G Member 2 Polymorphism ABCG2 c.421C>A Reduces Lamotrigine Trough Concentrations in Adults with Epilepsy.

Background and Objectives: The commonly used antiseizure medication lamotrigine is a substrate to ATP binding cassette subfamily G member 2 (ABCG2) transporter. The objective of this study was to evaluate the effect of the common loss-of-function polymorphism ABCG2 c.421C>A (rs2231142) on the lamotrigine trough concentrations at steady state in adults with epilepsy.
Methods: In two consecutive studies (Study 1, Study 2) in patients on lamotrigine monotherapy, carriers of the variant ABCG2 c.421C>A allele (CA/AA) were considered exposed, and wild-type homozygotes (CC) were considered controls. They were mutually balanced on covariates (age, sex, body weight, several polymorphisms in genes encoding other transporter proteins and lamotrigine-metabolizing enzymes that have been suggested to affect exposure to lamotrigine) to estimate the exposure effect (geometric means ratios, GMRs) in each study separately and overall (individual patient data meta-analysis). The overall estimate was evaluated for sensitivity to residual confounding.
Results: In both studies (exposed n = 28 vs. controls n = 103; exposed n = 44 vs. controls n = 153, in Study 1 and Study 2, respectively) and overall (exposed n = 72 vs. controls n = 256), dose-corrected lamotrigine trough concentrations were moderately lower in the exposed patients: frequentist GMR [95% CI] = 0.82 [0.63-1.08]; GMR = 0.69 [0.60-0.81] and GMR = 0.72 [0.63-0.83] in Study 1, Study 2 and overall, respectively; Bayes GMR [95% CrI] = 0.83 [0.68-1.00]; GMR = 0.69 [0.58-0.83] and GMR = 0.75 [0.65-0.86] in Study 1, Study 2 and overall, respectively. Estimates appeared resistant to unmeasured confounding-the E-values for the pooled point estimates were high, and estimates corrected for a strong hypothetical bias were GMR = 0.78 [0.68-0.90] frequentist and GMR = 0.81 [0.70-0.93] Bayes.
Conclusion: Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.
Competing Interests: Declarations. Funding: The studies presented in this report received no funding. Conflict of Interest: None of the authors have any conflict of interest to declare. The authors declare no support from any organization for the submitted work, no other financial relationships with any organizations that might have an interest in the submitted work, and no other relationships or activities that could appear to have influenced the submitted work. Author Contributions: The studies were conceived and designed by Nada Božina, Iva Klarica Domjanović, Ivana Šušak Sporiš and Vladimir Trkulja. Ivana Šušak Sporiš executed and supervised recruitment and management of most of the included patients. Lana Ganoci performed genetic analysis, Mila Lovrić pefromed lamotrigine measurements, and both were supervised by Nada Božina. Data were collected and assembled by Iva Klarica Domjanović, Ivana Šušak Sporiš, Lana Ganoci and Mila Lovrić. The present analysis was performed by Vladimir Trkulja who drafted the manuscript. Data were interpreted by Nada Božina and Vladimir Trkulja. All co-authors provided final approval of the manuscript. Ethics Approval: Both studies presented in this report were approved by the Institutional Ethics Committee (Study 1 – approval class: 8.1.-14/78-2, registration number: 02/21/JG, issued October 7, 2015; Study 2 – approval class: 8.1.-19/12-2, registration number: 02/21 AG, issued November 29, 2018). Consent to Participate: Only patients who signed a written informed consent for (1) genotyping for the pharmacogenes of interest and (2) publication of (anonymized) data for scientific purposes were included in the studies. Consent for Publication: Not applicable. Data Availability Statement: All data/datasets generated for the present analysis are available from the corresponding author upon a reasonable request. Code Availability: Codes used to generate frequentist (SAS for Windows 9.4) and Bayes estimates (R package rstanarm) are available from the corresponding author upon request.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)