title: Drug interactions and protease inhibitors used in the treatment of hepatitis C: how to manage?
abstract: OBJECTIVE
  The first-generation protease inhibitors (PI) boceprevir and telaprevir combined with pegylated interferon have revolutionized the treatment of type-1 hepatitis C by increasing the rates of sustained virologic response. However, they induce drug interactions, and their clinical relevance is difficult to predict. This review compiles available data on drug-drug interactions (DDI) based on their pharmacokinetic and pharmacodynamic properties with the aim of assisting clinicians in managing DDI METHODS: PubMed, drug interaction databases and hepatology and infectious disease conference abstracts were systematically searched using the key search terms "interaction", "hepatitis C", "telaprevir" and "boceprevir". All known interactions were compiled and reclassified according to their pharmacokinetic and pharmacodynamic mechanisms. The state of knowledge of interaction mechanisms are reported and a therapeutic approach is proposed.
  
  
  RESULTS
  Boceprevir and telaprevir are both substrates and potent inhibitors of cytochrome P450 3A4 and the drug transporter P-glycoprotein. They induce overdosage but can sometimes decrease the effect of other drugs by inducing other cytochromes. Overdosage or low dosage mainly affects drugs with a narrow therapeutic range, such as immunosuppressants or antiretrovirals. The distribution and elimination of PI are unaffected by interactions. In terms of pharmacodynamic interactions, PI can trigger drug-induced QT interval prolongation, which means that clinicians should manage such risk factors as potassium/magnesium levels or avoid other QT-prolonging drugs.
  
  
  CONCLUSIONS
  Management of hepatitis C therapy is complex. The key to interpreting DDI data is a solid understanding of the pharmacokinetic and pharmacodynamic profiles of the drugs involved. Their ability to inhibit cytochrome P450 3A4 and prolong the QT interval can have significant clinical consequences. This review provides a practical guide to the safe and effective management of therapy with boceprevir and telaprevir.
authors.affiliation: Department of Pharmacy, Clermont-Ferrand University Hospital, Clermont-Ferrand, France, stalavera@chu-clermontferrand.fr.
authors.forename: Sarah
authors.initials: S
authors.lastname: Talavera Pons
authors.forename: Geraldine
authors.initials: G
authors.lastname: Lamblin
authors.forename: Anne
authors.initials: A
authors.lastname: Boyer
authors.forename: Valérie
authors.initials: V
authors.lastname: Sautou
authors.forename: Armand
authors.initials: A
authors.lastname: Abergel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000493:pharmacokinetics; D004347:Drug Interactions; D018565:Food-Drug Interactions; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics*; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D015842:Serine Proteinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C486464:telaprevir; 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