A Review of Daclatasvir Drug–Drug Interactions

Abstract

The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug–drug interactions (DDIs). Daclatasvir (DCV)—the benchmark pangenotypic nonstructural protein 5A inhibitor—has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir. DCV may be the object of a DDI via the induction or inhibition of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) by the concomitant medication, or the precipitant of a DDI via DCV-based induction/inhibition of CYP 3A4 or inhibition of P-gp, organic anion transporting polypeptide 1B1/B3, and/or breast cancer resistance protein. This article presents an overview of the drug interaction studies conducted during the clinical development of DCV, the findings of these studies that led to the guidance on concomitant medication use and dosage along with any required DCV dose modifications, and the use of the known metabolic pathway of DCV to guide concomitant dosing where direct drug–drug studies have not been conducted. The robust characterization of the DCV clinical pharmacology program has demonstrated that DCV has few or no clinically relevant DDIs with medications with which it is likely to be co-administered, and the majority of DDIs that do occur can be predicted and easily managed. Funding: Bristol-Myers Squibb.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0407-5) contains supplementary material, which is available to authorized users.

The Drug-Drug Interaction Potential of Antiviral Agents for the Treatment of Chronic Hepatitis C Infection

“…The primary route of elimination for daclatasvir is the feces (88%), predominantly as the parent, with little renal excretion (6.6%). Daclatasvir is a substrate for CYP3A and P-gp and is an inhibitor of P-gp/BCRP and OAT1B1/3 (Garimella et al, 2016;Daklinza, 2017).…”

“…Sofosbuvir, ledipasvir, velpatasvir, and elbasvir are not expected to perpetrate any metabolic enzyme-mediated DDIs. Although daclatasvir may induce CYP3A, several clinical studies with coadministered CYP3A substrates have demonstrated that daclatasvir is unlikely to elicit clinically relevant interactions (Garimella et al, 2016).…”

Comments on “The Efficacy of 12 Weeks of Sofosbuvir, Daclatasvir, and Ribavirin in Treating Hepatitis C Patients with Cirrhosis, Genotypes 1 and 3”

“…Among Direct Acting Antiviral (DAA)-based treatment regimens for chronic HCV infection, the combination of daclatasvir and sofosbuvir has shown manageable interactions with anti-HIV drugs (7). Given the fact that daclatasvir is a substrate of CYP3A4 and that regimens containing etravirine and efavirenz decrease daclatasvir exposure through CYP3A4 induction, it seems necessary to increase the dose of daclatasvir to 90 mg daily in order to minimize the drug interactions (2,3,8).…”

“…Moreover, concomitant prescription of daclatasvir with antiretroviral regimens, which contain atazanavir/ritonavir and inhibit CYP3A4, would cause a 2.1-fold increase in the area under the curve (AUC) of daclatasvir (8). Likewise, a combination of atazanavir and cobicistat exhibits the same interactions with daclatasvir.…”

“…Likewise, a combination of atazanavir and cobicistat exhibits the same interactions with daclatasvir. Therefore, the dose of daclatasvir should be decreased to 30 mg daily when prescribed along with these antiretroviral drugs (2,3,8,9).…”