Methadone Pharmacokinetics and Cardiac Effects in Newborns
Condition: Pain
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      Painful procedures are frequent during the NICU care of sick newborns. Newborns are capable
      of perceiving pain by the time in fetal development when they reach our current limits of
      viability around 23-24 weeks post menstrual age.1 Painful procedures include suctioning
      during mechanical ventilation, thoracostomy tube placement, heel lance and venipuncture for
      blood sampling, and care following surgical procedures such as PDA ligation and bowel
      resection. Simons et al recently reported on the number of painful procedures in a large NICU
      in Rotterdam and provided a review of the frequency of such procedures from other NICU's.2
      This review shows that before discharge from the NICU, newborns may experience as many as 376
      painful procedures and as many as 61 painful procedures in a single day (or more if all
      procedures were not observed or reported). The most frequent procedures were heel lance and
      suctioning, both associated with the need for mechanical ventilation. Topical treatment of
      pain from heel lance has not been successful with EMLA3 or tetracaine.4

      During initial NICU care for infants supported with mechanical ventilation, systemic
      analgesia is usually provided with parenteral treatment with fentanyl or morphine. Most
      neonates are extubated soon after birth, and continued systemic treatment with analgesics is
      not needed. Other neonates have problems associated with chronic pain or continued painful
      procedures, such as surgical problems, chronic lung disease, airway anomalies, pulmonary
      hypoplasia and pulmonary hypertension following ECMO and congenital diaphragmatic hernia
      repair. These patients often require mechanical ventilation for weeks and sometimes months.
      During that prolonged care, systemic analgesia is changed to enteral dosing to reduce risks
      of infection associated with central catheters and to reduce the number of intravenous
      catheter insertions.

      Morphine and fentanyl administered enterally do not provide reliable systemic concentrations
      and effects due to first-pass metabolism. Fentanyl undergoes first-pass metabolism by CYP3A4
      during passage through the intestines and liver. Morphine undergoes first pass hepatic
      metabolism primarily by UGT2B7. In addition for morphine, one of its major metabolites, the
      3-glucuronide, is anti-analgesic and can cause dysphoria. An effective and well-characterized
      systemic analgesic that can be administered enterally is needed for the care of infants who
      require prolonged analgesic treatment and methadone can meet those needs.

      Methadone treatment in adults provides effective systemic analgesia after enteral
      administration through binding to the mu opioid receptor with a wide range of reported
      half-lives of 5 to 130 hrs,5 2 to 50 hrs,6 and 33 to 46 hrs; 7 and bioavailability ranging
      from 41 to 95%.8, 9

      Recently, methadone was reported to prolong QTc in adults receiving large doses of methadone
      during chronic treatment, often with additional predisposing factors for QT prolongation.
      Methadone is dispensed in a racemic mixture whose enantiomers have different potency for
      analgesia and for binding to the myocardium to potentially prolong QT. In addition the
      different enantiomers exhibit complex kinetics in adults as they undergo metabolism,
      primarily by CYP3A4, CYP2B6, and CYP2C19. This study will evaluate kinetics and
      bioavailability of methadone enantiomers and its effects on QT of neonates and young infants.
    

Intervention name(s): Methadone HCl Inject 10 mg/ml (will require dilution); Methadone
Intervention type(s): Drug; Drug
Intervention description(s): Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 mg/ml (will require dilution); Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution) Single dose
Other intervention name(s): Dolophine, Methadose, Methadose Oral; Dolophine, Methadose, Methadose Oral
Intervention MeSH terms: Methadone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Methadone; analgesia; newborns; QT prolongation; Young Infants