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Managing drug–drug interactions with new direct‐acting antiviral agents in chronic hepatitis C

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.