title: Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with fosamprenavir-ritonavir in opioid-dependent subjects.
abstract: OBJECTIVE
  To compare steady-state pharmacokinetics and pharmacodynamics of methadone enantiomers when coadministered with fosamprenavir 700 mg-ritonavir 100 mg twice/day.
  
  
  METHODS
  Open-label, single-sequence, two-period crossover, drug-interaction study.
  
  
  METHODS
  Two university-affiliated research centers.
  
  
  METHODS
  Twenty-six opioid-dependent, methadone-maintained, healthy adults.
  
  
  METHODS
  Subjects received their usual daily dose of methadone alone for 4 days (period 1). Subjects then received the same daily dose of methadone plus fosamprenavir 700 mg-ritonavir 100 mg twice/day for 14 days (period 2).
  
  
  RESULTS
  Blood was collected on days 1-4 (period 1) and on days 11-14 (period 2) for plasma R- and S-methadone concentrations; amprenavir concentrations were assessed during period 2. Opioid-effect measures were assessed in each study period. Subjects served as their own controls for comparison of period 1 with period 2. Coadministration of fosamprenavir-ritonavir with methadone reduced plasma total R-methadone area under the plasma concentration-time curve over the dosing interval at steady state (AUC tau-ss) by 18%, maximum concentration at steady state (Cmax-ss) by 21%, and concentration at the end of the dosing interval at steady state (Ctau-ss) by 11%; time to reach Cmax-ss (Tmax) was delayed by 1.75 hours. Coadministration of fosamprenavir-ritonavir with methadone also reduced plasma total S-methadone AUC tau-ss and Cmax-ss by 43% each, Ctau-ss by 41%, and delayed Tmax by 0.85 hours. Fosamprenavir-ritonavir administered with methadone did not alter plasma amprenavir pharmacokinetics compared with historical control data; nor did it alter the unbound R-methadone at 2 and 6 hours after methadone dosing. Pharmacodynamic indexes remained essentially unchanged after adding fosamprenavir-ritonavir to methadone. No subject demonstrated opioid intoxication or withdrawal, or requested methadone dosage modification.
  
  
  CONCLUSIONS
  No adjustment in the dosages of either methadone or fosamprenavir 700 mg-ritonavir 100 mg twice/day is required during coadministration, on the basis of the small reduction in total R-methadone exposure, no change in unbound R-methadone, no clinically important opioid effects, and no change in amprenavir exposure.
authors.affiliation: Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, Maryland 21287-5554, USA.
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Cao
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Wire
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Charles T
authors.initials: CT
authors.lastname: Lancaster
authors.forename: Roger C
authors.initials: RC
authors.lastname: Causon
authors.forename: George E
authors.initials: GE
authors.lastname: Bigelow
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martinez
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
authors.forename: Christine
authors.initials: C
authors.lastname: Radebaugh
authors.forename: Sarah
authors.initials: S
authors.lastname: McCabe
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D005663:Furans; D006801:Humans; D008297:Male; D008691:Methadone / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009294:Narcotics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010755:Organophosphates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D009294:Narcotics; D010755:Organophosphates; D011355:Prodrugs; D013449:Sulfonamides; C095108:amprenavir; D019438:Ritonavir; D008691:Methadone; C426859:fosamprenavir