Geneva Medical Faculty & University Hospitals of Geneva, Department of Pediatrics, Geneva, Switzerland.
Pharmacogenomics. 2011 Oct;12(10):1493-501. doi: 10.2217/pgs.11.91. Epub 2011 Sep 8.
To examine the safety profile of oseltamivir in children and evaluate the impact of P-glycoprotein polymorphisms on the incidence of neuropsychiatric adverse events (NPAE) in oseltamivir-treated children.
SUBJECTS & METHODS: This prospective cohort study was conducted in our tertiary care pediatric hospital (University Hospitals of Geneva, Switzerland) during the H1N1 pandemia, between 1 October 2009 and 31 January 2010. All newborn to 18 year-old patients presenting at the emergency department with a flu-like illness were eligible for inclusion. Adverse events were systematically recorded by pediatricians and/or by parents at home using a diary card, with a 30-day follow-up period. The causality assessment of oseltamivir in NPAE was performed by two clinical pharmacologists. After informed consent, enrolled patients were also genotyped for ABCB1 3435C>T (rs1045642) and 2677G>T/A (rs2032582) polymorphisms.
Among the 42 H1N1-infected, oseltamivir-treated children who were genotyped for ABCB1 3435C>T and 2677G>T/A variants, 36% presented NPAE. When examining the association between the diplotype and the development of NPAE, we observed that the frequency of NPAE displayed a 'genotype-trend effect' with the variant and the wild-type subgroups at the two far ends. A total of 11% of the 2677GG-3435CC individuals (wild-type homozygous) presented NPAE, compared with 39% of the individuals being heterozygous for at least one variant allele and 67% of the 2677TT-3435TT individuals (homozygous variants) (p = 0.149, nonsignificant).
These observations suggest a potential influence of ABCB1 polymorphisms in oseltamivir-related NPAE, maybe as a result of an enhanced permeability of the blood-brain barrier to oseltamivir
研究奥司他韦在儿童中的安全性，并评估 P-糖蛋白多态性对奥司他韦治疗儿童中神经精神不良事件（NPAE）发生率的影响。
这是一项在瑞士日内瓦大学附属医院进行的前瞻性队列研究，研究期间正值 H1N1 大流行（2009 年 10 月 1 日至 2010 年 1 月 31 日）。所有因流感样疾病就诊于急诊科的新生儿至 18 岁患者均符合纳入标准。儿科医生和/或家长使用日记卡在家中系统记录不良事件，并进行 30 天随访。两名临床药理学家通过评估奥司他韦与 NPAE 的因果关系。在获得知情同意后，入组患者还进行 ABCB1 3435C>T（rs1045642）和 2677G>T/A（rs2032582）多态性的基因分型。
在接受奥司他韦治疗的 42 例 H1N1 感染儿童中，有 36%的儿童出现了 NPAE。当检查二倍型与 NPAE 发生之间的关联时，我们观察到随着变体和野生型亚组处于两个极端，NPAE 的发生频率显示出“基因型趋势效应”。2677GG-3435CC 个体（野生型纯合子）中出现 NPAE 的比例为 11%，而至少携带一个变异等位基因的杂合子个体中为 39%，2677TT-3435TT 个体（纯合变异体）中为 67%（p=0.149，无显著性差异）。
这些观察结果表明，ABCB1 多态性可能对奥司他韦相关的 NPAE 有潜在影响，可能是由于奥司他韦对血脑屏障的通透性增强所致。
