Clinical trial NCT01327079: The Use of Methadone in Newborn Infants
Official title: Optimizing the Use of Methadone in Newborn Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Premature Birth of Newborn
Critically Ill
Keywords: NICU
Methadone
neonates
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
First posted: 2011-04-01
Enrollment: 60
Sex: ALL
Minimum age (years): 22
Maximum age (years): 43
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: This proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the CYP2B6 enzyme (as measured by the formation clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP in neonates is dependent on the glomerular filtration rate and therefore on the stage of development (defined by both gestational and postnatal age). The investigators propose to develop a PK model for methadone dosing in neonates that takes into account both developmental stage and genetic variability. The long-term goal of the proposed investigations is to improve dosing of methadone in neonates exposed to opioids in utero or post-natally, leading to improved control of their withdrawal syndrome and decreased adverse drug reactions associated with the current use of methadone in these vulnerable patients. More immediately, the investigators will develop a PK model for methadone dosing based on relevant developmental and genetic characteristics. The acquired knowledge based on the proposed study will lead to a more efficacious treatment of pain or opiate withdrawal syndrome in newborn infants with a decreased chance of adverse drug reactions.

Detailed description: The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates uniformly distributed with respect to gestational age and encompassing GA's of from 22 to less than 43 weeks.

* Stratified Selection by Gestational Age (GA): The study neonates will be selected to achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks, 31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad representation by GA. As described below, analyses will treat GA as a continuous variable.
* Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).
* Study medications: Methadone and inulin administration Blood and urine will be collected for the purposes of this research project. Blood will be drawn from the indwelling arterial catheter that already is in place for clinical purposes. The amount of blood obtained for all study related determinations will be minimized and kept at less than 3 mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours for group.
* DNA study 0.3ml whole blood will be collected from each subject
* PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0, 1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in 30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of methadone. A total of 1.5 ml of blood will be collected from each subject
* Urine Collection Urine samples will be collected from each infant's diaper (wood pulp based study diapers) every 3-4 hours over the first 24 hour period or alternatively, from an indwelling urinary catheter placed based on clinical indications unrelated to the study protocol.

Eligibility criteria: Inclusion Criteria:

* Newborn infants of both genders and all races who have:

  * a postnatal age of less than 3 months
  * an indwelling (peripheral or umbilical) arterial line, and
  * already treated with an opioid (morphine or fentanyl) for clinical reasons

Exclusion Criteria:

* Neonates with severe asphyxia grade III or IV intraventricular hemorrhage,
* Neonates with major congenital malformations or facial malformations (e.g., cleft lip and palate), neurological disorders
* Neonates receiving continuous or intermittent neuromuscular blockers neonates will be excluded who have:

  * clinical or biochemical evidence of hepatic and renal failure (including systemic hypoperfusion
  * received drugs that are CYP2B6 substrates
  * been exposed in utero to methadone, despite the fact that they indeed receive a CYP2B6 substrate through their mother, will not be excluded but will be analyzed as a subgroup

Primary outcomes:
measure: Methadone PK and EDDP
timeFrame: 36 months
Secondary outcomes:
measure: DNA
timeFrame: 36 months
Other outcomes:
Locations:
city: Washington
country: United States
facility: Childrens Research Institute
state: District of Columbia
city: Washington
country: United States
facility: Childrens's Research Institute
state: District of Columbia
Study officials:
References:
citation: van Donge T, Samiee-Zafarghandy S, Pfister M, Koch G, Kalani M, Bordbar A, van den Anker J. Methadone dosing strategies in preterm neonates can be simplified. Br J Clin Pharmacol. 2019 Jun;85(6):1348-1356. doi: 10.1111/bcp.13906. Epub 2019 Apr 10.