Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy
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...
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Frontiers Media S.A.
2019-07-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00832/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhan-zhang Wang Zhan-zhang Wang Yue-feng Zhang Wen-can Huang Wen-can Huang Xi-pei Wang Xiao-jiao Ni Hao-yang Lu Jin-qing Hu Shu-hua Deng Xiu-qing Zhu Huan-shan Xie Hong-zhen Chen Ming Zhang Chang Qiu Yu-guan Wen Yu-guan Wen De-wei Shang De-wei Shang |
spellingShingle |
Zhan-zhang Wang Zhan-zhang Wang Yue-feng Zhang Wen-can Huang Wen-can Huang Xi-pei Wang Xiao-jiao Ni Hao-yang Lu Jin-qing Hu Shu-hua Deng Xiu-qing Zhu Huan-shan Xie Hong-zhen Chen Ming Zhang Chang Qiu Yu-guan Wen Yu-guan Wen De-wei Shang De-wei Shang Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy Frontiers in Pharmacology lamotrigine Chinese population pharmacokinetics NONMEM epilepsy |
author_facet |
Zhan-zhang Wang Zhan-zhang Wang Yue-feng Zhang Wen-can Huang Wen-can Huang Xi-pei Wang Xiao-jiao Ni Hao-yang Lu Jin-qing Hu Shu-hua Deng Xiu-qing Zhu Huan-shan Xie Hong-zhen Chen Ming Zhang Chang Qiu Yu-guan Wen Yu-guan Wen De-wei Shang De-wei Shang |
author_sort |
Zhan-zhang Wang |
title |
Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy |
title_short |
Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy |
title_full |
Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy |
title_fullStr |
Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy |
title_full_unstemmed |
Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy |
title_sort |
effects of comedication and genetic factors on the population pharmacokinetics of lamotrigine: a prospective analysis in chinese patients with epilepsy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-07-01 |
description |
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. |
topic |
lamotrigine Chinese population pharmacokinetics NONMEM epilepsy |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00832/full |
work_keys_str_mv |
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doaj-f3add61c3fb74ffd974d71e977bd213e2020-11-24T21:15:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-07-011010.3389/fphar.2019.00832463478Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With EpilepsyZhan-zhang Wang0Zhan-zhang Wang1Yue-feng Zhang2Wen-can Huang3Wen-can Huang4Xi-pei Wang5Xiao-jiao Ni6Hao-yang Lu7Jin-qing Hu8Shu-hua Deng9Xiu-qing Zhu10Huan-shan Xie11Hong-zhen Chen12Ming Zhang13Chang Qiu14Yu-guan Wen15Yu-guan Wen16De-wei Shang17De-wei Shang18Department of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaGuangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, ChinaDepartment of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, Guangzhou Bureau of Civil Affairs Psychiatric Hospital, Guangzhou, ChinaMedical Research Center, Guangdong Province People’s Hospital, Guangdong Academy of Medical Sciences, Cardiovascular Institute, Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaGuangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, ChinaDepartment of Pharmacy, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, ChinaGuangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, ChinaLamotrigine (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.https://www.frontiersin.org/article/10.3389/fphar.2019.00832/fulllamotrigineChinesepopulation pharmacokineticsNONMEMepilepsy |