The optimization of methadone dosing whilst treating with rifampicin: A pharmacokinetic modeling study

Raj K.S. Badhan, Roz Gittins, Dina Al Zabit

Research output: Contribution to journalArticle

Abstract

Background
The use of oral methadone in opioid substitution treatment (OST) for the management of opioid use disorder is established clinical practice. Confounding treatment is the increased risks of contracting Mycobacterium tuberculosis, the mainstay treatment of which incorporates the potent CYP 2B6 inducer rifampicin.

Methods
This study applied pharmacokinetic modelling using virtual clinical trials, to pharmacokinetically quantify the extent and impact of rifampicin-mediated drug-drug interactions (DDI) on methadone plasma concentrations. An R-methadone model was developed and validated against 11 retrospective clinical studies prior to use in all subsequent studies. The aims were to investigate: (i) the impact of the DDI on daily methadone doses of 60 mg, 90 mg and 120 mg; (ii) dose escalation during rifampicin and (iii) dose reduction following rifampicin cessation.

Results
A dose increase to 160 mg daily during rifampicin treatment phases was required to maintain peak methadone plasma concentrations within a derived therapeutic window of 80–700 ng/mL. Dose escalation prior to rifampicin initiation was not required and resulted in an increase in subjects with supra-therapeutic concentrations. However, during rifampicin cessation, a dose reduction of 10 mg every 2 days commencing prior to rifampicin cessation, ensured that most patients possessed a peak methadone plasma concentration within an optimal therapeutic window.

Implications
Rifampicin significantly alters methadone plasma concentrations and necessitates dose adjustments. Daily doses of almost double those used perhaps more commonly in clinical practice are required for optimal plasma concentration and careful consideration of dose reduction strategies would be required during the deinduction phase.
Original languageEnglish
Pages (from-to)168-180
Number of pages13
JournalDrug and Alcohol Dependence
Volume200
Early online date20 May 2019
DOIs
Publication statusPublished - 1 Jul 2019

Fingerprint

Pharmacokinetics
Methadone
Rifampin
Plasmas
Drug interactions
Drug Interactions
Opioid Analgesics
Opiate Substitution Treatment
Therapeutics
Mycobacterium tuberculosis
Pharmaceutical Preparations
Substitution reactions
Retrospective Studies
Clinical Trials

Bibliographical note

© 2019, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Keywords

  • Dose
  • Methadone
  • Optimization
  • PBPK
  • Pharmacokinetics
  • Rifampicin

Cite this

Badhan, Raj K.S. ; Gittins, Roz ; Al Zabit, Dina. / The optimization of methadone dosing whilst treating with rifampicin : A pharmacokinetic modeling study. In: Drug and Alcohol Dependence. 2019 ; Vol. 200. pp. 168-180.
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The optimization of methadone dosing whilst treating with rifampicin : A pharmacokinetic modeling study. / Badhan, Raj K.S.; Gittins, Roz; Al Zabit, Dina.

In: Drug and Alcohol Dependence, Vol. 200, 01.07.2019, p. 168-180.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The optimization of methadone dosing whilst treating with rifampicin

T2 - A pharmacokinetic modeling study

AU - Badhan, Raj K.S.

AU - Gittins, Roz

AU - Al Zabit, Dina

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PY - 2019/7/1

Y1 - 2019/7/1

N2 - BackgroundThe use of oral methadone in opioid substitution treatment (OST) for the management of opioid use disorder is established clinical practice. Confounding treatment is the increased risks of contracting Mycobacterium tuberculosis, the mainstay treatment of which incorporates the potent CYP 2B6 inducer rifampicin.MethodsThis study applied pharmacokinetic modelling using virtual clinical trials, to pharmacokinetically quantify the extent and impact of rifampicin-mediated drug-drug interactions (DDI) on methadone plasma concentrations. An R-methadone model was developed and validated against 11 retrospective clinical studies prior to use in all subsequent studies. The aims were to investigate: (i) the impact of the DDI on daily methadone doses of 60 mg, 90 mg and 120 mg; (ii) dose escalation during rifampicin and (iii) dose reduction following rifampicin cessation.ResultsA dose increase to 160 mg daily during rifampicin treatment phases was required to maintain peak methadone plasma concentrations within a derived therapeutic window of 80–700 ng/mL. Dose escalation prior to rifampicin initiation was not required and resulted in an increase in subjects with supra-therapeutic concentrations. However, during rifampicin cessation, a dose reduction of 10 mg every 2 days commencing prior to rifampicin cessation, ensured that most patients possessed a peak methadone plasma concentration within an optimal therapeutic window.ImplicationsRifampicin significantly alters methadone plasma concentrations and necessitates dose adjustments. Daily doses of almost double those used perhaps more commonly in clinical practice are required for optimal plasma concentration and careful consideration of dose reduction strategies would be required during the deinduction phase.

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KW - Dose

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