The Use of Methadone in Newborn Infants

NCT01327079 | Completed Phase 1 DMC

• 2 other identifiers: 4781IV Methadone
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

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.

Conditions

Premature Birth of Newborn; Critically Ill

Keywords

NICU; Methadone; neonates

Outcome Measures

Primary Outcomes (1)

• Methadone PK and EDDP

  Primary outcome: Plasma and urine levels of methadone and EDDP (2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine, the main metabolite of methadone). Secondary endpoints: CYP2DB6 genetic variability.

  36 months

Secondary Outcomes (1)

• DNA

  36 months

Study Arms (2)

Group 1

EXPERIMENTAL

Gestational age less than 29 weeks We will substitute for one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Drug: Methadone

Group 2

EXPERIMENTAL

Gestational age greater then 29 weeks We will substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Drug: Methadone

Interventions

Methadone DRUG

If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone. Administration of inulin: Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Also known as: inulin

Group 1

Eligibility Criteria

• Age: 22 Weeks - 43 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• John van den Anker: lead

Study Sites (2)

Childrens Research Institute

Washington D.C., District of Columbia, 20010, United States

Location

Childrens's Research Institute

Washington D.C., District of Columbia, 20010, United States

Location

Related Publications (1)

• 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.

  PMID: 30805946 DERIVED

MeSH Terms

Conditions

Premature Birth; Critical Illness

Interventions

Methadone; Inulin; sinistrin

Condition Hierarchy (Ancestors)

Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ketones; Organic Chemicals; Starch; Glucans; Biopolymers; Polymers; Macromolecular Substances; Dietary Carbohydrates; Carbohydrates; Fructans; Polysaccharides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: John van denanker, MD, PhD

Study Record Dates

• First Submitted: March 30, 2011
• First Posted: April 1, 2011
• Study Start: December 1, 2010
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: July 26, 2018

Record last verified: 2018-07

Locations

US (2)