title: Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methadone.
abstract: OBJECTIVE
  To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone.
  
  
  METHODS
  Phase I, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study.
  
  
  METHODS
  Clinical research center.
  
  
  METHODS
  Fourteen volunteers receiving stable methadone maintenance therapy who were not infected with the human immunodeficiency virus.
  
  
  METHODS
  Tenofovir DF was added to the subjects' methadone regimens.
  
  
  RESULTS
  The pharmacokinetics of total, R-, and S-methadone were evaluated at baseline and after 2 weeks of daily tenofovir DF coadministration with a light meal. Steady-state tenofovir DF pharmacokinetics were evaluated at day 15. Bioequivalence testing was conducted of total, R-, and S-methadone area under the serum or plasma concentration-time curve during the 24-hour dosing interval at steady state (AUCss) and maximum concentration in serum or plasma (Cmax). Subjects were evaluated for changes in methadone pharmacodynamics by the Short Opiate Withdrawal Scale (SOWS) and pupillary diameter measurements at frequent intervals. Coadministration with tenofovir DF did not affect the pharmacokinetics of methadone. Geometric mean R-methadone systemic exposures, AUCss and Cmax, differed by 5% or less when methadone was dosed with tenofovir DF. Similar results were observed for S-methadone and for total methadone. Both AUCss and Cmax met the strict criteria for bioequivalence between the two study periods for total, R-, and S-methadone, indicating a lack of drug interaction when tenofovir DF was coadministered with methadone. No significant changes in SOWS scores or pupillary diameter measurements occurred, and no notable clinical adverse events were reported.
  
  
  CONCLUSIONS
  Tenofovir DF pharmacokinetics were comparable to previously reported values of tenofovir DF in HIV-infected patients. Coadministration of methadone with tenofovir DF did not alter the pharmacokinetics or pharmacodynamics of total, R-, or S-methadone. Tenofovir DF may be given as part of a once-daily antiretroviral regimen in patients receiving methadone maintenance therapy.
authors.affiliation: University at Buffalo School of Pharmacy and Pharmaceutical Sciences, New York 14260, USA. pfsmith@buffalo.edu
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
authors.forename: Sandra
authors.initials: S
authors.lastname: Liaw
authors.forename: Denise
authors.initials: D
authors.lastname: Cloen
authors.forename: Julie M
authors.initials: JM
authors.lastname: Bullock
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Haas
authors.forename: Kitty
authors.initials: K
authors.lastname: Yale
authors.forename: Brent M
authors.initials: BM
authors.lastname: Booker
authors.forename: Charles S
authors.initials: CS
authors.lastname: Berenson
authors.forename: Dion F
authors.initials: DF
authors.lastname: Coakley
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016001:Confidence Intervals; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008875:Middle Aged; D009294:Narcotics / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D013237:Stereoisomerism; D019966:Substance-Related Disorders / Q000534:rehabilitation; D000068698:Tenofovir
chemical_list: D009294:Narcotics; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D000068698:Tenofovir; D000225:Adenine; D008691:Methadone