PEDIATRICS Vol. 120 No. 3 September 2007, pp. 691-692 (doi:10.1542/peds.2007-1741)
LETTER TO THE EDITOR |
Timing of Dose-Finding Studies: Before or After Completion of a Randomized Clinical Trial?
John N. van den Anker, MD, PhDDepartment of Pediatrics
George Washington University
Washington, DC 20010
To the Editor.—
Ghanta et al1 reported that in preterm infants (median gestational age: 27–28 weeks; median postnatal age: 3–4 days), the use of propofol is more effective than a morphine, atropine, and suxamethonium regimen as an induction agent to facilitate neonatal nasal endotracheal intubation. In their well-designed randomized, controlled clinical trial, they used a single 2.5 mg/kg intravenous dose and based their selection of this specific dose on the recommended lowest bolus induction dose for propofol in adults and children >3 years old. As a neonatal clinical pharmacologist, I would like to know the rationale behind the selection of this specific dose for use in this vulnerable population without having any information on the pharmacokinetics of propofol in the studied population. Propofol is a highly lipophilic compound that exhibits a rapid distribution from the vascular compartment into the fat compartment including the central nervous system followed by redistribution to the vascular compartment and subsequent metabolism and excretion. Glucuronidation is the major metabolic pathway of propofol metabolism,2 and we know that development has a major impact on the glucuronidation capacity of the young infant.3,4 The use of chloramphenicol (also dependent for its metabolism on glucuronidation) in neonates resulted in a major therapeutic misadventure in the past on the basis of a developmentally decreased clearing capacity of the neonate.5
It all boils down to 1 basic question: Do we need to study the pharmacokinetics of propofol in neonates first to determine the dose to be used in a clinical trial, or do we conduct a clinical trial without having that information? I would like to be an advocate for preterm neonates in that we need to have an idea first of how neonates handle the drug before we use it in a randomized clinical trial. We do not want to expose preterm neonates to unnecessary risks. I propose that clinical researchers and pediatric clinical pharmacologists join forces and establish multidisciplinary teams to design and conduct safe and effective studies with medicines in the neonatal population.
REFERENCES
- Ghanta S, Abdel-Latif ME, Lui K, Ravindranathan H, Awad J, Oei J. Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial. Pediatrics. 2007;119(6) . Available at: www.pediatrics.org/cgi/content/full/119/6/e1248
- Favetta P, Degoute CS, Perdix JP, Dufresne C, Boulieu R, Guitton J. Propofol metabolites in man following propofol induction and maintenance.
Br J Anaesth. 2002;88
:653
–658
[Abstract/Free Full Text] - Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology: drug disposition, action, and therapy in infants and children.
N Engl J Med. 2003;349
:1157
–1167
[Free Full Text] - De Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36 :439 –452[CrossRef][Web of Science][Medline]
- Knight M. Adverse drug reactions in neonates. J Clin Pharmacol. 1994;34 :128 –135[Abstract]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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