ABSTRACT
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.
ABSTRACT
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 de?signs 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 da?ta 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.