Methadone Pharmacokinetics and Cardiac Effects in Newborns

NCT00715988 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 245691U10HD045986-01
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 2

Brief Summary

The Primary objectives of this proposal are to determine the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 weeks post menstrual age (PMA) who are 1 week old and older and establish any correlations of the kinetics with PMA to determine the bioavailability for enterally administered methadone in these newborns and young infants. The secondary objectives of this proposal are to explore possible genotypic changes in CYP3A4-3A7-3A5, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 and PGO on the kinetics of methadone in neonates and young infants and to test the safety of methadone in this population by correlating the plasma concentrations of the methadone enantiomers, S-methadone and R-methadone, with changes in cardiac repolarization by measurement of corrected QT, heart rate, and blood pressure.

Conditions

Pain

Keywords

Methadone; analgesia; newborns; QT prolongation; Young Infants

Outcome Measures

Primary Outcomes (1)

• Find the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 wks PMA who are 1 week old and older

  48 hours

Secondary Outcomes (1)

• Measure the effects of R and S enantiomers of methadone on QT interval in newborns

  48 hours

Study Arms (2)

Scheme 1

EXPERIMENTAL

Patients who are feeding or not feeding and mechanically ventilated, \>/=3 d of age and 29 0/7wks-48 6/7 wks PMA, treated with i.v. bolus doses or infusion of fentanyl, morphine or methadone for clinical indications, with arterial/venous line in place \& expected treatment for at least 1-2 more days. Pk sampling = 0.5 ml blood samples x6/infant. ECG monitoring. Three patients will be enrolled in 5 PMA groups. Should apnea or hypotension occur, dosages for Treatment Scheme 2 will be reduced (50%); more patients will be studied in Treatment Scheme 1 to insure that the lower dose is well tolerated \& effective.

Drug: Methadone

Scheme 2

EXPERIMENTAL

Patients defined in Scheme 1, tolerating feeds for \>/= 3 days will be studied twice, after i.v. methadone and after enteral methadone after the end of sampling after the first dose. 4-5 samples will be obtained after dose 1 and after dose 2 depending on PMA and weight. Patients will be divided into groups based on PMA..

Drug: Methadone HCl Inject 10 mg/ml (will require dilution)

Interventions

Methadone HCl Inject 10 mg/ml (will require dilution) DRUG

Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 mg/ml (will require dilution)

Also known as: Dolophine, Methadose, Methadose Oral

Scheme 2

Methadone DRUG

Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution) Single dose

Also known as: Dolophine, Methadose, Methadose Oral

Scheme 1

Eligibility Criteria

• Age: 29 Weeks - 48 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients must be in the NICU or PICU with continuous cardiorespiratory monitoring
• PMA between 29 0/7 to 48 6/7 weeks (EGA at birth (wks) + postnatal age wks) at the start of study
• Weight \>1499 gm at the time of enrollment
• Postnatal age of 3 days or more
• Arterial or venous catheter suitable for blood sampling with a separate i.v. infusion site is preferred, but not essential
• Currently being treated with methadone bolus doses or fentanyl or morphine in bolus doses or by infusion for clinical indications and expected to be treated for at least 1-2 more days with opioids for study of single dose pharmacokinetics and to be treated for 3-5 days more during the study of bioavailability
• Hematocrit ≥35%
• Parental permission
• Approval by the patient's attending physician
• Treatment Scheme 1, studied for 48 hr after a single i.v. dose of methadone
• Feeding or not feeding
• Mechanically ventilated
• Treatment Scheme 2 studied for 24 to 48 hr after a single i.v. dose of methadone AND again after a single enteral dose of methadone after the end of sampling after the first dose; order of doses is randomized. If the caregiver feels the patient is too sedated at the end of pK sampling after Dose, 1, then Dose 2 will be delayed until patient is judged to need analgesic treatment.
• Tolerating enteral feeding for 3 consecutive days before study

You may not qualify if:

• Clinically diagnosed liver dysfunction
• Clinically diagnosed kidney dysfunction with urine output \<1.0 ml/kg/hr
• Gastrointestinal malformation or dysfunction that might interfere with enteral drug absorption
• Congenital anomalies or other conditions thought to be incompatible with life
• History of arrhythmias, excluding bradycardia associated with apnea
• Unstable cardiorespiratory status
• Serum K+ \<3.0 mEq/L
• QTc\[H\] \>0.449 ms using Hodges correction =QT + 1.75(rate - 60).
• Family history of unexplained early cardiac deaths, syncope, or long QT syndrome in primary relatives: siblings, parents, grandparents, or aunts/uncles.
• Treatment with inhibitors and inducers of CYP3A4, CYP2B6, CYP2D6 and PGP including:
• amiodarone, carbamazepine, ciprofloxacin, clarithromycin, clotrimazole, dexamethasone, erythromycin, ethosuximide, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nelfinavir, paroxetine, phenobarbital, phenytoin, quercetin, quinidine, rifabutin, rifampin, ritonavir, saquinavir, sulfadimidine, sulfinpyrazone, troleandomycin

Sponsors & Collaborators

• University of Utah: lead
• Case Western Reserve University: collaborator
• Children's Mercy Hospital Kansas City: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (2)

University of Utah

Salt Lake City, Utah, 84108, United States

Location

Primary Children's Medical Center

Salt Lake City, Utah, 84113, United States

Location

Related Publications (1)

• Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.

  PMID: 24666686 DERIVED

MeSH Terms

Conditions

Pain; Agnosia; Long QT Syndrome

Interventions

Methadone

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Perceptual Disorders; Neurobehavioral Manifestations; Nervous System Diseases; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes

Intervention Hierarchy (Ancestors)

Ketones; Organic Chemicals

Study Officials

• Robert Ward, M.D.

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Pediatrics; Adjunct Professor, Pharmacology/Toxicology

Study Record Dates

• First Submitted: July 10, 2008
• First Posted: July 15, 2008
• Study Start: October 1, 2007
• Primary Completion: September 1, 2012
• Study Completion: February 10, 2017
• Last Updated: June 1, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share

Locations

US (2)