PDF(Pubmed)
Abstract：
UNASSIGNED: Precise estimation of a patient\'s drug metabolism capacity is important for antiseizure dose personalization.
UNASSIGNED: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.
UNASSIGNED: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.
UNASSIGNED: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.
UNASSIGNED: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.
UNASSIGNED: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.
UNASSIGNED: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.
UNASSIGNED: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.
UNASSIGNED: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.
UNASSIGNED: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.
UNASSIGNED: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.
UNASSIGNED: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.
UNASSIGNED: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.
UNASSIGNED: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.
UNASSIGNED: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.
摘要：
■精确估计患者的药物代谢能力对于抗癫痫剂量个性化很重要。
■量化与编码药物代谢酶的基因变体相关的抗癫痫药物的血浆浓度差异。
■PubMed,临床试验注册。欧盟，ClinicalTrials.gov,国际临床试验注册平台，和CENTRAL数据库在1990年1月1日至2023年9月30日的研究中进行了筛选,没有语言限制.
两名评审员进行了独立的研究筛选，并评估了以下纳入标准：进行了适当的基因分型，基于基因型的分类为亚组是可能的，每个亚组至少有3名参与者.
■遵循流行病学观察性研究（MOOSE）指南的荟萃分析进行数据提取和后续质量，有效性，和偏见风险评估。纳入研究的结果与随机效应荟萃分析进行汇总。
■用浓度-时间曲线下的剂量归一化面积对抗癫痫药物的血浆浓度进行定量，剂量归一化的稳态浓度，或标准剂量和采样时间单剂量后的浓度。通过将药物遗传学变体的载体和非载体的平均药物血浆浓度除以计算平均值的比率。
■来自98项研究的数据，涉及12543名接受苯妥英治疗的成年参与者，丙戊酸盐,拉莫三嗪,或卡马西平进行了分析。研究主要在东亚（69项研究）或白人或欧洲（15项研究）队列中进行。与参考亚组相比，观察到苯妥英的血浆浓度显着增加，CYP2C9中间代谢者的46%(95%CI，33%-61%)，CYP2C19中间代谢物的20%（95%CI，17%-30%），CYP2C19代谢不良者为39%（95%CI，24%-56%）；丙戊酸盐，CYP2C9中间代谢者的12%(95%CI，4%-20%)，CYP2C19中间代谢者的12%（95%CI，2%-24%），CYP2C19代谢不良者占20%（95%CI，2%-41%）；卡马西平，CYP3A5代谢不良者的12%（95%CI，3%-22%）。
■这项系统评价和荟萃分析发现，CYP2C9和CYP2C19基因型编码低酶容量与苯妥英血浆浓度的临床相关增加有关，几种药物遗传学变异与丙戊酸盐和卡马西平血药浓度的统计学显著相关，但仅有轻微的临床相关变化，许多药物遗传学变异与抗癫痫药物的血浆浓度无统计学显著差异。
■量化与编码药物代谢酶的基因变体相关的抗癫痫药物的血浆浓度差异。
■PubMed,临床试验注册。欧盟，ClinicalTrials.gov,国际临床试验注册平台，和CENTRAL数据库在1990年1月1日至2023年9月30日的研究中进行了筛选,没有语言限制.
两名评审员进行了独立的研究筛选，并评估了以下纳入标准：进行了适当的基因分型，基于基因型的分类为亚组是可能的，每个亚组至少有3名参与者.
■遵循流行病学观察性研究（MOOSE）指南的荟萃分析进行数据提取和后续质量，有效性，和偏见风险评估。纳入研究的结果与随机效应荟萃分析进行汇总。
■用浓度-时间曲线下的剂量归一化面积对抗癫痫药物的血浆浓度进行定量，剂量归一化的稳态浓度，或标准剂量和采样时间单剂量后的浓度。通过将药物遗传学变体的载体和非载体的平均药物血浆浓度除以计算平均值的比率。
■来自98项研究的数据，涉及12543名接受苯妥英治疗的成年参与者，丙戊酸盐,拉莫三嗪,或卡马西平进行了分析。研究主要在东亚（69项研究）或白人或欧洲（15项研究）队列中进行。与参考亚组相比，观察到苯妥英的血浆浓度显着增加，CYP2C9中间代谢者的46%(95%CI，33%-61%)，CYP2C19中间代谢物的20%（95%CI，17%-30%），CYP2C19代谢不良者为39%（95%CI，24%-56%）；丙戊酸盐，CYP2C9中间代谢者的12%(95%CI，4%-20%)，CYP2C19中间代谢者的12%（95%CI，2%-24%），CYP2C19代谢不良者占20%（95%CI，2%-41%）；卡马西平，CYP3A5代谢不良者的12%（95%CI，3%-22%）。
■这项系统评价和荟萃分析发现，CYP2C9和CYP2C19基因型编码低酶容量与苯妥英血浆浓度的临床相关增加有关，几种药物遗传学变异与丙戊酸盐和卡马西平血药浓度的统计学显著相关，但仅有轻微的临床相关变化，许多药物遗传学变异与抗癫痫药物的血浆浓度无统计学显著差异。
