title: Pharmacokinetic interaction between telaprevir and methadone.
abstract: Hepatitis C virus (HCV) antibody is present in most patients enrolled in methadone maintenance programs. Therefore, interactions between the HCV protease inhibitor telaprevir and methadone were investigated. The pharmacokinetics of R- and S-methadone were measured after administration of methadone alone and after 7 days of telaprevir (750 mg every 8 h [q8h]) coadministration in HCV-negative subjects on stable, individualized methadone therapy. Unbound R-methadone was measured in predose plasma samples before and during telaprevir coadministration. Safety and symptoms of opioid withdrawal were evaluated throughout the study. In total, 18 subjects were enrolled; 2 discontinued prior to receiving telaprevir. The minimum plasma concentration in the dosing interval (C(min)), the maximum plasma concentration (Cmax), and the area under the plasma concentration-time curve from h 0 (time of administration) to 24 h postdose (AUC(0-24)) for R-methadone were reduced by 31%, 29%, and 29%, respectively, in the presence of telaprevir. The AUC0-24 ratio of S-methadone/R-methadone was not altered. The median unbound percentage of R-methadone increased by 26% in the presence of telaprevir. The R-methadone median (absolute) unbound C(min) values in the absence (10.63 ng/ml) and presence (10.45 ng/ml) of telaprevir were similar. There were no symptoms of opioid withdrawal and no discontinuations due to adverse events. In summary, exposure to total R-methadone was reduced by approximately 30% in the presence of telaprevir, while the exposure to unbound R-methadone was unchanged. No symptoms of opioid withdrawal were observed. These results suggest that dose adjustment of methadone is not required when initiating telaprevir treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT00933283.).
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium. rvheesw1@its.jnj.com
authors.forename: Rolf
authors.initials: R
authors.lastname: van Heeswijk
authors.forename: Peter
authors.initials: P
authors.lastname: Verboven
authors.forename: Ann
authors.initials: A
authors.lastname: Vandevoorde
authors.forename: Petra
authors.initials: P
authors.lastname: Vinck
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.forename: Griet
authors.initials: G
authors.lastname: Boogaerts
authors.forename: Els
authors.initials: E
authors.lastname: De Paepe
authors.forename: Rodica
authors.initials: R
authors.lastname: Van Solingen-Ristea
authors.forename: James
authors.initials: J
authors.lastname: Witek
authors.forename: Varun
authors.initials: V
authors.lastname: Garg
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; 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*; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D058850:Opiate Substitution Treatment; D013237:Stereoisomerism; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control
chemical_list: D000998:Antiviral Agents; D009294:Narcotics; D009842:Oligopeptides; C486464:telaprevir; D008691:Methadone