The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics

John J. McCarthy, Ernest J. Vasti, Martin H Leamon, Joseph Graas, Coburn Ward, Catherine Fassbender

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objectives: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. Methods: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. Results: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P=0.007), and then rose significantly from trimester 3 to postpartum (P=0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. Conclusions: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.

Original languageEnglish (US)
Pages (from-to)241-246
Number of pages6
JournalJournal of Addiction Medicine
Volume12
Issue number3
DOIs
StatePublished - Jan 1 2018

Fingerprint

Methadone
Pharmacokinetics
Serum
Postpartum Period
Pregnancy
Enzyme Induction
Opioid Analgesics
Mothers
Safety

Keywords

  • CYP450
  • metabolic ratio
  • methadone/metabolite
  • pharmacokinetics
  • pregnancy

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics. / McCarthy, John J.; Vasti, Ernest J.; Leamon, Martin H; Graas, Joseph; Ward, Coburn; Fassbender, Catherine.

In: Journal of Addiction Medicine, Vol. 12, No. 3, 01.01.2018, p. 241-246.

Research output: Contribution to journalArticle

McCarthy, John J. ; Vasti, Ernest J. ; Leamon, Martin H ; Graas, Joseph ; Ward, Coburn ; Fassbender, Catherine. / The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics. In: Journal of Addiction Medicine. 2018 ; Vol. 12, No. 3. pp. 241-246.
@article{803a1c37a2af47548c86ff35c1240a3a,
title = "The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics",
abstract = "Objectives: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. Methods: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. Results: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P=0.007), and then rose significantly from trimester 3 to postpartum (P=0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8{\%} to 30{\%} to 38{\%} across trimesters, and decreased to 5{\%} postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. Conclusions: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.",
keywords = "CYP450, metabolic ratio, methadone/metabolite, pharmacokinetics, pregnancy",
author = "McCarthy, {John J.} and Vasti, {Ernest J.} and Leamon, {Martin H} and Joseph Graas and Coburn Ward and Catherine Fassbender",
year = "2018",
month = "1",
day = "1",
doi = "10.1097/ADM.0000000000000398",
language = "English (US)",
volume = "12",
pages = "241--246",
journal = "Journal of Addiction Medicine",
issn = "1932-0620",
publisher = "Lippincott Williams and Wilkins",
number = "3",

}

TY - JOUR

T1 - The Use of Serum Methadone/Metabolite Ratios to Monitor Changing Perinatal Pharmacokinetics

AU - McCarthy, John J.

AU - Vasti, Ernest J.

AU - Leamon, Martin H

AU - Graas, Joseph

AU - Ward, Coburn

AU - Fassbender, Catherine

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objectives: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. Methods: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. Results: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P=0.007), and then rose significantly from trimester 3 to postpartum (P=0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. Conclusions: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.

AB - Objectives: Pregnancy profoundly alters drug metabolism, accelerating clearance and confounding medication management, primarily through induction of CYP450 enzymes. Methadone is a CYP450 substrate with altered pharmacokinetics during pregnancy. We report on the use of serum methadone/metabolite ratios (MMRs) to monitor changes in methadone metabolism through the perinatal period and to objectively guide methadone dosing. Previous research found average MMRs in nonpregnant populations of between 11.3 and 12.7. Methods: Serum methadone and its major metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine concentrations were analyzed in 67 samples from 23 pregnant patients treated for opioid use disorder, and their calculated ratio was used to document changes in methadone clearance across trimesters and postpartum. Lower ratios indicate increased clearance. Results: The average MMR during pregnancy was 6.1. Ratios declined significantly from trimester 1 to trimester 3 (P=0.007), and then rose significantly from trimester 3 to postpartum (P=0.001). The per cent of ratios that were 4 or less, indicating ultrarapid metabolism, increased from 8% to 30% to 38% across trimesters, and decreased to 5% postpartum. Forty-four per cent of individual patients had at least 1 prepartum ratio of 4 or less. Conclusions: This study documents significant metabolic changes occurring perinatally, which indicate the need for both changes in methadone dose and dose frequency to maintain maternal/fetal stability, and also dose reductions as hypermetabolism reverses postpartum. MMRs provide an objective tool to more efficiently improve the safety and efficacy of methadone dosing perinatally.

KW - CYP450

KW - metabolic ratio

KW - methadone/metabolite

KW - pharmacokinetics

KW - pregnancy

UR - http://www.scopus.com/inward/record.url?scp=85048150346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048150346&partnerID=8YFLogxK

U2 - 10.1097/ADM.0000000000000398

DO - 10.1097/ADM.0000000000000398

M3 - Article

C2 - 29521669

AN - SCOPUS:85048150346

VL - 12

SP - 241

EP - 246

JO - Journal of Addiction Medicine

JF - Journal of Addiction Medicine

SN - 1932-0620

IS - 3

ER -