Methadone Pharmacokinetics and Cardiac Effects in Newborns

• Status: Completed
• Trial end date: 2017-02-10
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Utah
• Collaborators: Case Western Reserve University; Children's Mercy Hospital Kansas City; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Treatments: Methadone

Criteria

INCLUSION CRITERIA

1. Patients must be in the NICU or PICU with continuous cardiorespiratory monitoring

2. PMA between 29 0/7 to 48 6/7 weeks (EGA at birth (wks) + postnatal age wks) at the start of study

3. Weight >1499 gm at the time of enrollment

4. Postnatal age of 3 days or more

5. Arterial or venous catheter suitable for blood sampling with a separate i.v. infusion site is preferred, but not essential

6. 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

7. Hematocrit ≥35%

8. Parental permission

9. Approval by the patient's attending physician

Treatment Scheme 1, studied for 48 hr after a single i.v. dose of methadone

10. Feeding or not feeding

11. 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.

12. Tolerating enteral feeding for 3 consecutive days before study

EXCLUSION CRITERIA

1. Clinically diagnosed liver dysfunction

2. Clinically diagnosed kidney dysfunction with urine output <1.0 ml/kg/hr

3. Gastrointestinal malformation or dysfunction that might interfere with enteral drug absorption

4. Congenital anomalies or other conditions thought to be incompatible with life

5. History of arrhythmias, excluding bradycardia associated with apnea

6. Unstable cardiorespiratory status

7. Serum K+ <3.0 mEq/L

8. QTc[H] >0.449 ms using Hodges correction =QT + 1.75(rate - 60).

9. Family history of unexplained early cardiac deaths, syncope, or long QT syndrome in primary relatives: siblings, parents, grandparents, or aunts/uncles.

10. 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