title: Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C.
abstract: Several direct-acting antiviral agents (DAAs) have marketing authorization in Europe and in the USA and have changed the landscape of hepatitis C treatment: each DAA has its own metabolism and drug-drug interactions (DDIs), and managing them is a challenge. To compile the pharmacokinetics and DDI data of the new DAA and to provide a guide for management of DDI. An indexed MEDLINE search was conducted using the keywords: DAA, hepatitis C, simeprevir, daclatasvir, ledipasvir, sofosbuvir, 3D regimen (paritaprevir/ritonavir, ombitasvir, dasabuvir), DDI and pharmacokinetics. Data were also collected from hepatology, and infectious disease and clinical pharmacology conferences abstracts. Food can play a role in the absorption of DAAs. Most of the interactions are linked to metabolism (cytochrome P450-3 A4 [CYP3A4]) or hepatic and/or intestinal transporters (organic anion-transporting polypeptide and P-glycoprotein [P-gp]). To a lesser extent other pathways can be involved such as breast cancer resistance protein transporter or UDP-glucuronosyltransferase metabolism. DDI are more likely to occur with 3D regimen, daclatasvir, simeprevir and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir. They can increase concentrations of coadministered drugs and their concentrations may be influenced by P-gp or CYP3A4 inducers or inhibitors. Overdosage or low dosage can be encountered with potent inducers or inhibitors of CYP3A4 or drugs with a narrow therapeutic range. The key to interpret DDI data is a good understanding of the pharmacokinetic profiles of the drugs involved. Their ability to inhibit CYP450-3A4 and transporters (hepatic and/or intestinal) can have significant clinical consequences.
authors.affiliation: Service de Pharmacie Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Talavera Pons
authors.affiliation: Service de Pharmacie Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boyer
authors.affiliation: Service de Médecine Digestive et Hépato-biliaire Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Lamblin
authors.affiliation: Service de Pharmacie Centre Hospitalier Universitaire, Clermont-Ferrand, France.|EA 4676 C-Biosenss, Université d'Auvergne, Clermont-Ferrand, Cedex, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Chennell
authors.affiliation: Service de Pharmacie Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: François-Thibault
authors.initials: FT
authors.lastname: Châtenet
authors.affiliation: Service de Médecine Digestive et Hépato-biliaire Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Nicolas
authors.affiliation: Service de Pharmacie Centre Hospitalier Universitaire, Clermont-Ferrand, France.|EA 4676 C-Biosenss, Université d'Auvergne, Clermont-Ferrand, Cedex, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Sautou
authors.affiliation: Service de Médecine Digestive et Hépato-biliaire Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France.|Unité Mixte de Recherche Université d'Auvergne, CNRS 6284, University of Clermont-Ferrand, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Abergel
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D018565:Food-Drug Interactions; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D027361:Organic Anion Transporters / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D027361:Organic Anion Transporters; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: direct-acting antiviral; drug-drug interaction; hepatitis C; management