The recognition that pain is experienced by preterm infants and that adequate pain management can improve both short and long term outcomes has led to the more common use of pain controlling substances in this vulnerable population. Recently, an increasing appreciation for opioid-associated adverse events has prompted an increase in the use of acetaminophen (APAP) for treating pain in preterm neonates. However, there is far less information available concerning developmental aspects of metabolism and potential toxicity of APAP in preterm neonates as compared to full term infants, children and adults. In addition, very recent data have shown that elevations of APAP-CYS (a specific biomarker for APAP toxicity) in serum occur not only in association with severe APAP overdose but even, after therapeutic exposure of APAP in adults. In order to enhance the safety and efficacy of APAP use in preterm neonates, there is a need for an improved understanding of the developmental and pharmacogenetic determinants of age-associated differences in the metabolism and potential toxicity of APAP in this vulnerable population. The measurement of APAP-CYS combined with the use of metabolomic profiling and urine and serum metabolomics to identify toxicity-associated drug metabolite profiles or new biomarkers will provide new information pertinent to assessing the safety of APAP in preterm neonates. The clinical investigations proposed in this application have the following aims: 1. To evaluate the relationship of developmental stage (defined by both gestational, and postnatal age) to UDP-glucuronosyltransferase 1A6 (UGT1A6) and sulfotransferase 1A1 (SULT1A1) activity. 2. To evaluate the relationship of glomerular filtration rate to the elimination clearances of acetaminophen (APAP), APAP-glucuronide and APAP-sulphate, at different developmental stage (as measured by gestational and postnatal age) of the preterm neonate. 3. To evaluate the relationship of UGT1A6 genotype to UGT1A6 phenotype, and the relationship of SULT1A1 genotype to SULT1A1 phenotype. 4. To evaluate the relationship of developmental stage (defined by both gestational and postnatal age) to APAP-associated toxicities (as measured by the formation of APAP-CYS and other novel APAP toxicity- associated biomarkers) and the combined relationship to cumulative APAP dose.

Public Health Relevance

The use of intravenous acetaminophen (APAP) in preterm infants will increase significantly in the coming years, despite the fact that APAP is the major cause of liver failure in the US. To assure safe use of APAP in this vulnerable population, this research proposal will investigate the impact of development on metabolism and toxicity of APAP in preterm infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD060543-05
Application #
8687697
Study Section
Special Emphasis Panel (ZRG1-CB-L (50))
Program Officer
Giacoia, George
Project Start
2010-08-10
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$292,626
Indirect Cost
$102,426
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Cook, Sarah F; Roberts, Jessica K; Samiee-Zafarghandy, Samira et al. (2016) Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation. Clin Pharmacokinet 55:107-19
Samiee-Zafarghandy, S; van den Anker, J N; Laughon, M M et al. (2016) Sildenafil and retinopathy of prematurity risk in very low birth weight infants. J Perinatol 36:137-40
Allegaert, Karel; van den Anker, John N (2016) Neonatal pain management: still in search for the Holy Grail. Int J Clin Pharmacol Ther 54:514-23
Allegaert, Karel; Mekahli, Djalila; van den Anker, John (2015) Cystatin C in newborns: a promising renal biomarker in search for standardization and validation. J Matern Fetal Neonatal Med 28:1833-8
Cook, Sarah F; King, Amber D; van den Anker, John N et al. (2015) Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacok J Chromatogr B Analyt Technol Biomed Life Sci 1007:30-42
Samiee-Zafarghandy, Samira; Raman, Sudha R; van den Anker, John N et al. (2015) Safety of milrinone use in neonatal intensive care units. Early Hum Dev 91:31-5
Allegaert, K; van den Anker, J (2015) Neonatal drug therapy: The first frontier of therapeutics for children. Clin Pharmacol Ther 98:288-97
Ward, Robert M; Allegaert, Karel; de Groot, Ronald et al. (2014) Commentary: Continuous infusion of vancomycin in neonates: to use or not to use remains the question. Pediatr Infect Dis J 33:606-7
Allegaert, Karel; van den Anker, John N (2014) Neonatal abstinence syndrome: on the evidence to add breastfeeding to any clinical pathway. Pediatr Crit Care Med 15:579-80
De Cock, Roosmarijn F W; Allegaert, Karel; Brussee, Janneke M et al. (2014) Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res 31:2643-54

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