Understanding the determinants of analgesic response in newborns and children remains elusive, in part, due to lack of a single pharmacologic and molecular probe to elucidate the interindivual differences in opiod responsiveness across the entire developmental spectrum. Thus, safe and effective analgesia remains an unmet medical need in children. Codeine, the most commonly used opioid analgesic worldwide, undergoes metabolic activation, and can be potentially developed as a molecular probe and as an oral analgesic in neonates. The NICHD Pediatric Pharmacology Research Unit Network (PPRU) proposes a large initiative to evaluate the pharmacologic basis for the observed interindividual differences in opioid responsiveness in newborns and children. Initially, 9 PPRU sites will conduct a single- dose, open-label clinical trial in 64 mechanically ventilated term and preterm neonates born e 26 weeks gestational age with birth weight >700 grams and who are already receiving an opioid for pain management at various postnatal ages.
The specific aims of this proposal are threefold: 1) To determine the absorption and bioavailability of codeine in relation to postnatal and postconceptional age (PCA) 2) to determine the parent drug (codeine), its active metabolites, their formation rates and their ratios in relation with PCA and PNA and 3) to identify relevant genetic polymorphisms of opioid metabolism in this population and their potential relationship to the biodisposition and pharmacodynamic effects of codeine. Following a single oral dose of codeine, blood and urine samples will be collected for assay of codeine and its metabolites.Demographic, pharmacokinetic(PK), pharmacodynamic (PD)and pharmacogenetic data will be obtained. The primary PK outcomes are the rate and extent of absorption of oral codeine, the ratios of the concentration of each metabolite to the concentration of parent drug and the formation and clearances of the metabolites with particular emphasis on morphine and morphine- 6-glucuronide as functions of neonatal maturity (PNA, PCA) . Genotype analysis will comprise CYP2D6 and UGT2B7, the two major enzymes involved in the biotransformation of codeine and morphine. If the newborn infants can absorb and metabolize codeine, there is an opportunity to use a single molecular probe to elucidate the demographic, PK, PD and PG determinants of opioid responsiveness across all ages and to develop rational approaches to the management of pain in newborns and children. Pain management in newborn and children is a primary focus in healthcare, therefore understanding the mechanisms underlying pain control is of significant relevance to public health. If the newborn infants can absorb and metabolize codeine, there is an opportunity to use a single molecular probe to elucidate the demographic, PK, PD and PG determinants of opioid responsiveness across all ages and to develop rational approaches to the management of pain in newborns and children.
