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.
| Smits, Anne; van den Anker, John N; Allegaert, Karel (2017) Clinical pharmacology of analgosedatives in neonates: ways to improve their safe and effective use. J Pharm Pharmacol 69:350-360 |
| Samardzic, Janko; Allegaert, Karel; Wilbaux, Mélanie et al. (2016) Quantitative clinical pharmacology practice for optimal use of antibiotics during the neonatal period. Expert Opin Drug Metab Toxicol 12:367-75 |
| Allegaert, Karel; van den Anker, John N (2016) Neonatal withdrawal syndrome: reaching epidemic proportions across the globe. Arch Dis Child Fetal Neonatal Ed 101:F2-3 |
| Janssen, Esther J H; Välitalo, Pyry A J; Allegaert, Karel et al. (2016) Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling. Antimicrob Agents Chemother 60:1013-21 |
| Jancic, Jasna; Nikolic, Blazo; Ivancevic, Nikola et al. (2016) Multiple Sclerosis in Pediatrics: Current Concepts and Treatment Options. Neurol Ther 5:131-143 |
| Knøsgaard, Katrine Rørbæk; Foster, David John Richard; Kreilgaard, Mads et al. (2016) Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model. Eur J Pharm Sci 92:117-30 |
| Samardzic, Janko; Smits, Anne; Spriet, Isabel et al. (2016) Different Vancomycin Immunoassays Contribute to the Variability in Vancomycin Trough Measurements in Neonates. Biomed Res Int 2016:1974972 |
| Valitalo, Pyry A J; van den Anker, John N; Allegaert, Karel et al. (2015) Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates. J Antimicrob Chemother 70:2074-7 |
| 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, Karel; Cosaert, Katrien; van den Anker, John N (2015) Neonatal Formulations: The Need for a Tailored, Knowledge Driven Approach. Curr Pharm Des 21:5674-9 |
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