The Use of Methadone in Newborn Infants
| Status: | Completed |
|---|---|
| Conditions: | Hospital, Women's Studies |
| Therapuetic Areas: | Other, Reproductive |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 7/28/2018 |
| Start Date: | December 2010 |
| End Date: | December 2017 |
Optimizing the Use of Methadone in Newborn Infants
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.
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.
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.
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.
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
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