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

Abstract

Keywords direct-acting antiviral, drug-drug interaction, hepatitis C, management 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.British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) 83 269-293 269

Glycyrrhizin has a high likelihood to be a victim of drug–drug interactions mediated by hepatic organic anion‐transporting polypeptide 1B1/1B3

“…OATP1B1 and OATP1B3 display a large inhibitor overlap, which is in agreement with the high (80%) amino acid sequence homology between the two transporters (Karlgren et al ., ; Menon et al ., ). There are many dual inhibitors of OATP1B1/1B3 in clinical use, including some direct‐acting antiviral agents (DAAs) in hepatitis C virus infection treatment (Karlgren et al ., ; Furihata et al ., ; Talavera Pons et al ., ). Clinical drug–drug interaction study by Zha et al .…”

Efficacy and safety outcomes of sofosbuvir-based treatment regimens for hepatitis C virus-infected patients with or without cirrhosis from phase III clinical trials

“…However, each DAA has its own metabolic pathways and DDIs; therefore, managing DDIs before they occur is important to provide better antiviral potency, improved safety, and increased drug adherence. Most DDIs are associated with metabolism, especially by CYP3A4 and hepatic/intestinal transporters, such as organic anion-transporting polypeptide and P-gp 15. Based on data found in Micromedex ® Solutions, which is a drug information database, the major DDIs between DAAs and other drugs are summarized in Table 3.…”

“…Each DAA has its own metabolic pathway and exhibits different drug–drug interactions (DDIs); thus, management of DDIs and AEs is critical in clinical practice. Most DDIs are associated with cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (P-gp) activities 15. The induction or inhibition of CYP3A4 or P-gp may cause abnormal DAA exposure, thereby negatively affecting efficacy and safety.…”

Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

“…AL‐335) with an NS5A inhibitor (eg, odalasvir) with or without an NS3A/4 protease inhibitor (eg, simeprevir) may be a potentially effective combination that allows for short duration treatment (eg, ≤8 weeks) of chronic HCV infection. However, administering three DAAs in combination may give rise to the development of complex DDIs that can affect the concentrations of coadministered drugs . Determining the potential for DDIs is therefore important to inform decisions regarding dose selection of each of the components within a given combination.…”