Interaction between<i>ABCG2 421C&gt;A</i>polymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Domjanović, Iva Klarica; Lovrić, Mila; Trkulja, Vladimir; Petelin-Gadže, Željka; Ganoci, Lana; Čajić, Ivana; Božina, Nada

doi:10.1111/bcp.13646

Cited by 25 publications

(18 citation statements)

References 55 publications

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“…These studies have combined several simplistic situations including polymorphisms or polymorphisms plus VPA, which may not have been sufficient to distinguish and weigh multiple factors in practical use. In our final model, ABCG2 421C > A had no effect on LTG concentrations, similarly to the results of the Domjanovic et al study (Domjanovic et al, 2018), whereas ABCG2 34G > A was found to be a significant covariate.…”

Section: Discussionsupporting

confidence: 87%

“…However, the current opinion on whether ABCG2 421C > A is a predictor of LTG concentration remains controversial. Zhou et al (2015) and Shen et al (2016) have observed similar associations between ABCG2 -421AA and higher dose-normalized LTG concentrations in patients by using multiple linear regression models; in contrast, Domjanovic et al (2018) have demonstrated that the ABCG2 421A allele has no effect on LTG concentrations, but the variant allele effect would increase with incremental VPA troughs. These studies have combined several simplistic situations including polymorphisms or polymorphisms plus VPA, which may not have been sufficient to distinguish and weigh multiple factors in practical use.…”

Section: Discussionmentioning

confidence: 81%

“…The overexpression of ATP-binding cassette sub-family B member 1 (ABCB1; MDR1; P-glycoprotein 170) and breast cancer resistance protein (BCRP; ABCG2), major human efflux transporters for LTG at the blood–brain barrier, have been shown to be important mechanisms of pharmacoresistance in patients with epilepsy (Romermann et al, 2015). Efforts have been made to investigate the effects of MDR1 and ABCG2 transporters’ polymorphism on LTG pharmacokinetics in humans (Lovric et al, 2012; Zhou et al, 2015; Shen et al, 2016; Domjanovic et al, 2018). MDR1 rs1128503 and rs1045642 and ABCG2 rs2231142, rs3114020, and rs2231137 have been found to be associated with the disposition of LGT (Lovric et al, 2012; Zhou et al, 2015; Shen et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…MDR1 rs1128503 and rs1045642 and ABCG2 rs2231142, rs3114020, and rs2231137 have been found to be associated with the disposition of LGT (Lovric et al, 2012; Zhou et al, 2015; Shen et al, 2016). However, some of these findings are conflicting and require further investigation (Shen et al, 2016; Domjanovic et al, 2018). The organic cation transporter 1 (OCT1, encoded by the SLC22A1 gene), expressed primarily in epithelial cells, also suggests a major role of the membrane transporter in the pharmacokinetics of many organic cationic compounds (Arimany-Nardi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

et al. 2019

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Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1 -1222AA carriers. Patients with the ABCG2 -34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1 -2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

et al. 2019

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“…Finally, the variables used in our model, though readily available, are all non-genetic factors. The effects of genetic polymorphisms on LTG pharmacokinetics have been widely explored in previous studies, but have yielded some conflicting findings 48,49 . Thus, more variables (e.g., genetic factors) needed to be included in the model.…”

Section: Discussionmentioning

confidence: 99%

A machine learning approach to personalized dose adjustment of lamotrigine using noninvasive clinical parameters

Zhu

Huang

et al. 2021

Sci Rep

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The pharmacokinetic variability of lamotrigine (LTG) plays a significant role in its dosing requirements. Our goal here was to use noninvasive clinical parameters to predict the dose-adjusted concentrations (C/D ratio) of LTG based on machine learning (ML) algorithms. A total of 1141 therapeutic drug-monitoring measurements were used, 80% of which were randomly selected as the "derivation cohort" to develop the prediction algorithm, and the remaining 20% constituted the "validation cohort" to test the finally selected model. Fifteen ML models were optimized and evaluated by tenfold cross-validation on the "derivation cohort,” and were filtered by the mean absolute error (MAE). On the whole, the nonlinear models outperformed the linear models. The extra-trees’ regression algorithm delivered good performance, and was chosen to establish the predictive model. The important features were then analyzed and parameters of the model adjusted to develop the best prediction model, which accurately described the C/D ratio of LTG, especially in the intermediate-to-high range (≥ 22.1 μg mL−1 g−1 day), as illustrated by a minimal bias (mean relative error (%) = + 3%), good precision (MAE = 8.7 μg mL−1 g−1 day), and a high percentage of predictions within ± 20% of the empirical values (60.47%). This is the first study, to the best of our knowledge, to use ML algorithms to predict the C/D ratio of LTG. The results here can help clinicians adjust doses of LTG administered to patients to minimize adverse reactions.

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Bearing variant alleles at uridine glucuronosyltransferase polymorphisms UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) has no relevant consequences for lamotrigine troughs in adults with epilepsy

Božina

Sporiš

Domjanović

et al. 2023

Eur J Clin Pharmacol

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Purpose. To estimate whether epilepsy patients with variant UGT2B7 -161C>T(rs7668258) or UGT1A4*3 c.142T>G(rs2011425) alleles differ from their wild-type (wt) peers in exposure to lamotrigine.Methods. Consecutive adults on lamotrigine monotherapy or lamotrigine+valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C>T and UGT1A4*3 c.142T>G. Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of e ux transporter proteins ABCG2 c.421C>A (rs2231142) and ABCB1 1236C>T (rs1128503), and level of exposure to valproate using covariate entropy balancing.Results. Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in UGT2B7 -161C>T heterozygous (CT, n=237) or variant homozygous (TT, n=115) subjects were closely similar to those in their wt controls (CC, n=119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86-1.16) and 1.00 (95%CrI 0.83-1.22) for CT vs. CC; and 0.97 (0.81-1.17) and 0.97 (0.80-1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in UGT1A4*3 c.142T>G variant carriers [n=106: 102 TG + 4 GG subjects) and wt controls (TT, n=365): GMR= 0.95 (0.81-1.12) frequentist, 0.96 (0.80-1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate. Conclusion. Dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 -161C>T or UGT1A4*3 c.142T>G alleles are equivalent to those in their respective wt peers.

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Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

Abstract: This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.

Cited by 25 publications

References 55 publications

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy

A machine learning approach to personalized dose adjustment of lamotrigine using noninvasive clinical parameters

Bearing variant alleles at uridine glucuronosyltransferase polymorphisms UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) has no relevant consequences for lamotrigine troughs in adults with epilepsy

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