Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical
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ORIGINAL RESEARCH
Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical Response to Caffeine Citrate in Chinese Preterm Infants Xin He
. Jin-Chun Qiu
Ling Li
. Wei-Wei Jia . Ming-Ming Ni . Yun Liu . Jing Xu
Feng Chen
. Ke-Yu Lu . Hong-Li Guo
. .
. Rui Cheng
Received: September 1, 2020 / Accepted: October 20, 2020 Ó Springer Healthcare Ltd., part of Springer Nature 2020
ABSTRACT Introduction: 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. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12325020-01544-2) contains supplementary material, which is available to authorized users. X. He J.-C. Qiu H.-L. Guo M.-M. Ni J. Xu F. Chen (&) Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China e-mail: [email protected] K.-Y. Lu Y. Liu R. Cheng (&) Neonatal Intensive Care Unit, Children’s Hospital of Nanjing Medical University, Nanjing, China e-mail: [email protected] L. Li School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China W.-W. Jia State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Methods: 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. Eightyeight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system. Results: 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 (C0/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. Conclusions: Genetic polymorphisms in caffeine’s target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine
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