The pharmacological treatment of pain in pre-term neonates is complicated by a large inter-individual variability in the amount of analgesic medicines required for adequate pain relief. As a consequence it is difficult to predict the effective analgesic dose of morphine in individual critically ill pre-term neonates. In a recent large-scale NIH study (NEOPAIN), the use of """"""""customary"""""""" mg/kg therapeutic doses resulted in a high incidence of serious adverse drug events including hypotension and urinary retention. This was associated with extremely high (500 ng/ml vs therapeutic concentrations of 20-40 ng/ml) morphine plasma concentrations. In order to enhance the safety and efficacy of pain treatment in pre-term neonates, there is the need for an improved understanding of the developmental and pharmacogenetic determinants of age-associated differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine in this vulnerable population. The clinical investigations proposed in this project have the following specific aims: 1). To evaluate the relationship of developmental stage (defined by both gestational and postnatal age) to the activity of the morphine metabolizing enzyme UDP-glucuronosyltransferase 2B7 (UGT2B7) (as determined by the formation clearances (morphine to morphine-3-glucuronide (M3G) [CLf,M3G], and morphine to morphine-6-glucuronide (M6G) [CLf,M6G]). 2). To evaluate the relationship of UGT2B7 genetic variability to UGT2B7 activity (as determined by CLf,M3G and CLf,M6G). 3). To evaluate the relationship of glomerular filtration rate to the elimination clearances of morphine, M3G and M6G (CLother, CLM3G and CLM6G) and morphine concentrations in both blood and urine. 4). To evaluate the relationship of genetic variability in the mu-opioid receptor gene and the catechol-O-methyltransferase (COMT) gene to clinical response following administration of morphine and 5). To develop a population PK/PD model of morphine dosing based on gestational age, postnatal age, glomerular filtration rate, and genetic variability in the UGT2B7, mu-opioid receptor and COMT genes.
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