title: Potential P-glycoprotein pharmacokinetic interaction of telaprevir with morphine or methadone.
abstract: Telaprevir (TVR) effects on P-glycloprotein and cytochrome P450 (CYP) may significantly elevate serum levels of morphine and methadone. Recent literature points to major interactions when combining TVR with warfarin or rifampin. Opioid interactions are especially dangerous in hepatitis C patients, as coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs in 50-90% of HIV-infected drug users that are prescribed opioids for chronic pain and/or methadone for maintenance. TVR has been shown to significantly inhibit the active transport enzyme pGP and may therefore increase intestinal morphine absorption. TVR also inhibits hepatic CYP3A4 that are responsible for metabolizing methadone. Patients requiring opioid analgesics must be carefully monitored because of potential for elevated opioid levels and overdose risk. Current recommendations minimize potential drug interactions between telaprevir and opioids, especially methadone, based on a single 7-day trial. We outline the various pharmacokinetic mechanisms involved when combining TVR with methadone or morphine and recommend that current data are not sufficiently robust to minimize the potentially significant interaction with opioids, especially methadone. Clinicians must be mindful of these understated interactions, know that the opioid dose may need to be significantly increased or reduced, and use caution during upward titration of opioids affected by these enzyme systems.
authors.affiliation: Pharmacy Service, Stratton VA Medical Center, Pharmacy Service, 113 Holland Avenue, Albany, NY 12208, USA. jeff.fudin@acphs.edu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fudin
authors.forename: Dania Vanesta
authors.initials: DV
authors.lastname: Fontenelle
authors.forename: Hannah Rebecca
authors.initials: HR
authors.lastname: Fudin
authors.forename: Cynthia
authors.initials: C
authors.lastname: Carlyn
authors.forename: Debra Ann
authors.initials: DA
authors.lastname: Hinden
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Ashley
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D062787:Drug Overdose; D006801:Humans; D008691:Methadone / Q000009:adverse effects / Q000493:pharmacokinetics*; D009020:Morphine / Q000009:adverse effects / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D009842:Oligopeptides; C486464:telaprevir; D009020:Morphine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008691:Methadone