儿童药代动力学研究中的挑战和应对策略

Challenges and strategies in pediatric pharmacokinetic study

长期以来,儿科治疗被认为是"孤儿领域"。儿科治疗中经常出现超说明书使用药物,增加了治疗无效或发生毒性反应的风险。儿童(尤其是婴幼儿)药代动力学(PK)研究中面临许多天然存在的挑战,包括知情同意率低、可用于PK研究的血量少、采血困难、微量灵敏的分析手段有限、科学先进的拟合模型较少等。目前可获得的影响药物吸收、分布、代谢和排泄过程的各发育阶段儿童的生理因素仍十分有限。为应对这些挑战,迫切需要以创新思维开发适合这一脆弱群体的有效试验方案设计。本文总结最近的文献报道,综述各种用于描述儿童药物PK特征的风险最小化方法。微量采样、稀疏采样、再利用采样(机会性采样)、干血斑采样和非血基质采样等策略逐渐应用于幼儿。自上而下的群体PK模型适用于稀疏样品的统计分析;自下而上的PBPK模型提供了药物处置内在规律的认识,但二者都需要更全面的确证。充分理解现有的技术和模型的优势和劣势,有助于提高儿童PK研究方案设计的创新性和科学性。

Till now,pediatric populations are still described as＂therapeutic orphans＂,in which＂off-label＂and unlicensed use of drugs are common,increasing the risk of drug toxicity and suboptimal efficacy. The challenges inherent to performing clinical pharmacokinetic（PK）trials in pediatric populations,especially in the neonatal to infant stages,include：low study consent rates;limited blood volume;difficulty in obtaining blood;limited use of sensitive,low-volume drug concentration assays;a lack of expertise in pediatric modeling and simulation;and knowledge gap in the effects of dynamic physiological changes with growth and development on the absorption,disposition,metabolism and excretion of drugs. In response to these concerns,innovative and efficient study designs more suited to this population are needed. This review summarizes the available literature to describe the minimal-risk strategies in pediatric PK studies,such as micro-sampling,sparse sampling,scavenge sampling（opportunistic sampling）,dried blood spots sampling,and non-blood matrices sampling. Population PK modeling,referred to as a‘top-down＇approach,is able to analyze the data from sparse sampling,while the bottom up methods（physiologically based pharmacokinetic modeling）provides valuable insight in drug disposition,but both still needs more prospective validation. Understanding of the strengths and limitations of these methods will help improve the design of future pediatric PK studies.