阿利吉仑和依那普利在儿童体内药代动力学和药效学研究的定制分析方法：在血清、尿液和唾液中的应用
Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva.
作者信息
Burckhardt Bjoern B, Tins Jutta, Ramusovic Sergej, Läer Stephanie
机构信息
Department of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-University, Düsseldorf, Germany.
出版信息
J Pediatr Pharmacol Ther. 2015 Nov-Dec;20(6):431-52. doi: 10.5863/1551-6776-20.6.431.
OBJECTIVES
Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups.
METHODS
Tailored assays were developed for pharmacokinetic investigation of a drug in 100 μL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point.
RESULTS
The pharmacokinetic results of aliskiren and enalapril obtained by low-volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin-angiotensin-aldosterone system and to compare those results with the published literature.
CONCLUSION
These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy.
目的
有效用于治疗成人高血压的药物（如依那普利）在儿童中尚未得到充分研究。儿科批准所需的研究在伦理、研究设计和实施方面需要特殊考虑，并且对生物分析方法也有特殊要求。适合儿科的检测方法可以克服这些负担，并能够对所有儿科年龄组的药代动力学和药效学进行系统研究。
方法
开发了定制检测方法，用于在100μL血清、唾液和尿液中对一种药物进行药代动力学研究。所有检测方法都应用于一项概念验证研究，该研究纳入了22名健康志愿者，他们分别服用了300mg阿利吉仑半富马酸盐或20mg马来酸依那普利，并进行了密集采样。每次还在2.1mL血液中评估肾素 - 血管紧张素 - 醛固酮系统的6个体液参数变化。
结果
通过血清和尿液中的小体积检测方法获得的阿利吉仑和依那普利的药代动力学结果与文献中报道的结果相当。密集采样能够得到非常详细的浓度 - 时间曲线，显示出阿利吉仑受试者间变异性高和双相吸收行为。对于这两种药物，用唾液采集替代侵入性采样似乎不合适，因为两种体液中药物浓度的相关性较低。还使用小体积检测方法来测定肾素 - 血管紧张素 - 醛固酮系统的值，并将这些结果与已发表的文献进行比较。
结论
这些结果支持在儿科研究中使用小体积检测方法，并支持对其在新生儿和婴儿中的应用进行系统研究。使用这种检测方法将增加有关该脆弱人群药物药代动力学和药效学的信息，并可能有助于安全有效地使用药物治疗。
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