Drug interactions with new hepatitis C oral drugs

Abstract

Interactions between DAA and other drugs are frequent in clinical practice. The most frequent drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposures. Through this mechanism HCV protease inhibitors, especially when co-formulated with ritonavir as pharmacoenhancer, and non-nucleoside HCV polymerase inhibitors interact with other medications. In contrast, NS5B nucleos(t)ide analog inhibitors (i.e., sofosbuvir) and some HCV NS5A inhibitors (i.e., ledipasvir), which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions. However, exposure to HCV nucleos(t)ide analogs may be influenced by induction/inhibition of drug transporters (i.e., P-glycoprotein) as well as by pharmacodynamic interference with other nucleos(t)ide analogs used as antivirals or cancer drugs. Drug interactions for some NS5A inhibitors (i.e., daclatasvir) are generally moderate and can be managed with dose adjustments.

Direct-Acting Antivirals (DAAs): Drug-Drug Interactions (DDIs) in the Treatment of Hepatitis C Virus (HCV)

“…This review is focused on drug-drug interactions in the treatment of HCV infections in past several years. Adapted according to [8][9][10]. Table 1.…”

“…DDIs are more likely to occur with 3D regimen, followed by daclatasvir, simeprevir, and ledipasvir, as they are all both substrates and inhibitors of P-gp and/or CYP3A4, than with sofosbuvir [8][9][10]. Their concentrations may be inluenced by CYP3A4 and P-gp inducers or inhibitors or they can increase concentrations of coadminstered drugs.…”

“…Their concentrations may be inluenced by CYP3A4 and P-gp inducers or inhibitors or they can increase concentrations of coadminstered drugs. Low dose or overdosage can be expected with potent inducers or inhibitors of drugs with narrow therapeutic range [8][9][10].…”

Mechanisms of Virologic Failure with Direct-Acting Antivirals in Hepatitis C and Strategies for Retreatment

“…LDV is also a substrate of pgP; thus, drugs that induce the transporter protein pathway should also be avoided. 40 The key to achieving adequate serum levels of LDV and GS-5816 is an acid-rich environment in the gut. 40 Hence, proton pump inhibitor use may pose a problem.…”

Meet the Classes of Directly Acting Antiviral Agents

“…32 Drug-drug interactions may occur with nucleoside/nucleotide analogues when combined with drugs that inhibit or induce the p-glycoprotein transporter or other nucleoside analogues such as chemotherapeutic or antiviral agents. 33 Based on animal data, the currently approved nucleotide inhibitor sofosbuvir has a pregnancy safety class B rating.…”