Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.
Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China.
Adv Ther. 2021 Jan;38(1):607-626. doi: 10.1007/s12325-020-01544-2. Epub 2020 Nov 12.
Apnoea of prematurity (AOP) is among the most common diagnoses in the neonatal intensive care unit. Caffeine treatment is a preferred treatment choice. However, neonatal caffeine therapy results in significant intersubject variability. This study aimed to determine the effects of plasma caffeine levels based on standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants.
This single-center and retrospective study examined data from 112 preterm infants (< 35 weeks gestational age) between July 2017 and July 2018. Subjects were divided into apnoea-free (n = 48) and apnoeic (n = 64) groups, and their clinical outcomes were summarized. Liquid chromatography-tandem mass spectrometry was used to measure levels of caffeine and its primary metabolites. Eighty-eight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system.
Preterm infants in the apnoea-free group were associated with a reduction in the incidence of bronchopulmonary dysplasia and a reduced requirement for patent ductus arteriosus ligation. No significant association was observed between plasma-trough-concentration-to-dose (C/D) ratio and birth weight, gestational age, or postnatal age in either group. Polymorphisms in CYP1A2 and aryl hydrocarbon receptor (AHR) genes did not affect plasma caffeine levels. Polymorphisms in adenosine receptor genes ADORA1 (rs10920568 and rs12744240), ADORA2A (rs34923252 and rs5996696), and ADORA3 (rs10776727 and rs2298191), especially in AHR (rs4410790) and adenosine deaminase (rs521704), play critical roles in the interindividual response to caffeine therapy.
Genetic polymorphisms in caffeine's target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine therapy in preterm neonates. Future studies are needed to uncover how these genetic variants affect responses to caffeine therapy in this patient population.
早产儿呼吸暂停（AOP）是新生儿重症监护病房中最常见的诊断之一。咖啡因治疗是首选的治疗方法。然而，新生儿咖啡因治疗会导致显著的个体间变异性。本研究旨在确定基于标准剂量和遗传变异性的血浆咖啡因水平对中国早产儿接受柠檬酸咖啡因治疗的临床反应的影响。
这项单中心、回顾性研究分析了 2017 年 7 月至 2018 年 7 月期间 112 例（<35 周胎龄）早产儿的数据。受试者分为无呼吸暂停（n=48）和呼吸暂停（n=64）组，并总结其临床结局。采用液相色谱-串联质谱法测定咖啡因及其主要代谢物的水平。通过 MassARRAY 系统选择 88 个单核苷酸多态性进行基因分型。
无呼吸暂停组的早产儿支气管肺发育不良发生率降低，动脉导管未闭结扎需求减少。在两组中，血浆谷浓度与剂量（C/D）比值与出生体重、胎龄或生后年龄均无显著相关性。CYP1A2 和芳烃受体（AHR）基因的多态性不影响血浆咖啡因水平。腺苷受体基因 ADORA1（rs10920568 和 rs12744240）、ADORA2A（rs34923252 和 rs5996696）和 ADORA3（rs10776727 和 rs2298191）以及 AHR（rs4410790）和腺苷脱氨酶（rs521704）的多态性在个体对咖啡因治疗的反应中起关键作用。
咖啡因作用靶点的遗传多态性，而不是基于标准剂量的暴露水平，与早产儿对咖啡因治疗的个体反应差异相关。需要进一步的研究来揭示这些遗传变异如何影响该患者人群对咖啡因治疗的反应。
