title: Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, HIV-seronegative subjects.
abstract: BACKGROUND
  Dolutegravir (DTG) is an investigational integrase inhibitor for treatment of HIV infection. As intravenous drug use is a common risk factor for HIV, this study evaluated the effect of DTG on the pharmacokinetics (PK) of methadone.
  
  
  METHODS
  This was an open-label, 2-period study in adult, opioid-dependent, HIV-seronegative subjects. Subjects received their current individual methadone doses once daily for 3 days (Period 1) followed by DTG 50mg twice daily (BID) for 5 days while continuing their stable methadone therapy (Period 2). Serial PK samples for R- and S-methadone were collected after each Period. Pharmacodynamic (PD) measures and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated.
  
  
  RESULTS
  Plasma exposures of total, R-, and S-methadone were not affected by co-administration of DTG. Mean ratios for AUC were 0.98, 0.95, and 1.01 for total, R-, and S-methadone, respectively, alone compared with in combination with DTG. No statistically significant differences were noted between the 2 treatment periods in methadone PD measures. The combination of DTG and methadone was well tolerated. No deaths, serious adverse events, or grade 3/4 adverse events occurred. No clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed.
  
  
  CONCLUSIONS
  Co-administration of methadone with repeat doses of DTG 50mg BID had no effect on total, R-, and S-methadone PK or on methadone-induced PD markers. No dose adjustment in methadone is required when given in combination with DTG.
authors.affiliation: GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Stephen
authors.initials: S
authors.lastname: Mark
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Savina
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Wajima
authors.forename: Amanda
authors.initials: A
authors.lastname: Peppercorn
authors.forename: Urmilla
authors.initials: U
authors.lastname: Bala
authors.forename: Pierre
authors.initials: P
authors.lastname: Geoffroy
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D018023:HIV Seronegativity; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008691:Methadone / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects / Q000493:pharmacokinetics*; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders / Q000378:metabolism*; D010078:Oxazines; D010879:Piperazines; D011680:Pupil / Q000187:drug effects; D011728:Pyridones; D015819:Substance Abuse, Intravenous; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D008691:Methadone; D009294:Narcotics; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: Dolutegravir; Drug interaction; Methadone; Pharmacokinetics