title: Warfarin and boceprevir interaction causing subtherapeutic international normalized ratio: a case report.
abstract: BACKGROUND
  Chronic hepatitis C is a leading cause of severe liver disease. Protease inhibitors used to treat these patients are known to have many drug interactions, although there is limited data available between boceprevir and warfarin. This case report is the first in vivo drug interaction reported in the literature.
  
  
  METHODS
  A 73-year-old African American man was diagnosed with hepatitis C in 2004, and had decided to not initiate therapy. In 2006, he was diagnosed with deep vein thrombosis and pulmonary embolism and was started on warfarin. His international normalized ratio had been stable on a dose of 13.75 mg to 20mg/week over a period of 6 years. A liver biopsy in 2012 revealed marked fibrosis, leading the patient to start hepatitis C treatment with peginterferon alfa-2a, ribavirin and boceprevir. Three weeks after starting boceprevir, his international normalized ratio became subtherapeutic at 1.2. Upon increasing the warfarin dose by 16%, his international normalized ratio remained at 1.2 6 days later. Two months after initiating boceprevir, he reached a therapeutic international normalized ratio. His warfarin dose had been increased by 75% from his dose prior to starting boceprevir, from 15 mg/week to 26.25mg/week. His hepatitis C treatment was discontinued at week 39 of the intended 48 weeks of treatment due to severe thrombocytopenia. Upon discontinuation of boceprevir, his warfarin dose was prophylactically decreased by 17%, which resulted in a subtherapeutic international normalized ratio of 1.48 1 week later. The warfarin dose was subsequently increased by 10% which resulted, 2 weeks later, in a therapeutic international normalized ratio of 2.8. Once stabilized, his new warfarin dose was 23.75 mg/week, 37% higher than his original maintenance dose of 15 mg/week prior to starting boceprevir.
  
  
  CONCLUSIONS
  The co-administration of boceprevir and warfarin resulted in a subtherapeutic international normalized ratio. Upon starting boceprevir, his warfarin dose was increased by 75% over 2 months to achieve a therapeutic international normalized ratio. After discontinuing boceprevir, his maintenance dose of warfarin was 37% greater than his original dose. This is an original case report which demonstrates the significant effects of this drug interaction and the importance of monitoring international normalized ratio.
authors.affiliation: Clinical Pharmacist, Critical Care, VA New Jersey Healthcare System, East Orange, NJ, USA. atsiattalos@gmail.com.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tsiattalos
authors.forename: Anita
authors.initials: A
authors.lastname: Patel
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline