Division of Clinical Pharmacology and Medical Toxicology, The Childrens Mercy Hospitals and Clinics, Kansas City, Missouri 64108, USA.
Paediatr Drugs. 2011 Feb 1;13(1):19-31. doi: 10.2165/11536950-000000000-00000.
Across much of the world, pandemic H1N1 infection has produced a significant healthcare crisis, reflected in significant morbidity and mortality. Statistics reveal that infection-associated deaths among individuals without pre-existing conditions (e.g. immunosuppression) are clustered in pregnant women and young infants. In developing countries where the availability of influenzae vaccine is limited, the only currently available pharmacologic counter-measure for H1N1 disease is oseltamivir, a neuraminidase inhibitor with excellent in vitro activity against the virus. This drug is available in oral solid and liquid formulations, has excellent peroral bioavailability in adults, and generally has a very favorable safety profile. Many observational studies indicate that oseltamivir treatment is associated with symptomatic improvement in pediatric patients with H1N1 infection and, therefore, is considered to represent a viable therapeutic option for use in children. However, the disposition of the ethyl ester prodrug and its active metabolite has not been well characterized in infants and children. Presently, data are available from only two published investigations and preliminary summary information from a recent presentation of an ongoing study. Given that recent in vitro data support the importance of a target exposure-response profile for the active metabolite of oseltamivir and that many processes known to modulate drug disposition have a developmental basis, understanding the potential impact of age on oseltamivir disposition becomes crucial in the development of age-appropriate dosing regimens for the drug. In this review, the impact of ontogeny on processes that are important in regulating the absorption, distribution, metabolism, and excretion of oseltamivir and its active metabolite are considered. Data from both animal and human investigations are presented in the context of defining how development might influence the dose-exposure relationship and, most importantly, the significant variability associated with it. In addition, the available pediatric pharmacokinetic data for oseltamivir and its active metabolite are summarized and current 'information gaps' deserving of future study are presented.
在世界上的许多地方，大流行 H1N1 感染造成了重大的医疗保健危机，表现在发病率和死亡率方面。统计数据显示，没有潜在疾病（例如免疫抑制）的个体中，与感染相关的死亡病例集中在孕妇和婴儿身上。在流感疫苗供应有限的发展中国家，目前针对 H1N1 疾病的唯一可用药物对策是奥司他韦，这是一种对病毒具有出色体外活性的神经氨酸酶抑制剂。该药物有口服固体制剂和液体制剂，在成人中具有极好的口服生物利用度，并且通常具有非常有利的安全性。许多观察性研究表明，奥司他韦治疗与 H1N1 感染的儿科患者的症状改善有关，因此被认为是儿童治疗的可行选择。然而，在婴儿和儿童中，乙基酯前药及其活性代谢物的处置尚未得到很好的描述。目前，只有两项已发表的研究提供了数据，并且从最近正在进行的一项研究的初步总结信息中提供了数据。鉴于最近的体外数据支持奥司他韦活性代谢物的目标暴露-反应谱的重要性，并且许多已知调节药物处置的过程具有发育基础，因此了解年龄对奥司他韦处置的潜在影响在药物的年龄适当剂量方案的开发中变得至关重要。在这篇综述中，考虑了个体发生对调节奥司他韦及其活性代谢物的吸收、分布、代谢和排泄的重要过程的影响。呈现了来自动物和人类研究的数据，以确定发育如何影响剂量-暴露关系，最重要的是，与剂量-暴露关系相关的重要变异性。此外，总结了奥司他韦及其活性代谢物的可用儿科药代动力学数据，并提出了目前值得进一步研究的“信息差距”。
