Drug Interactions Between Hepatoprotective Agents Ursodeoxycholic Acid or Glycyrrhizin and Ombitasvir/Paritaprevir/Ritonavir in Healthy Japanese Subjects

Abstract

Purpose: The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen.

Methods: DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC).

Findings: After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change).

Implications: No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen.

Keywords: drug interactions; glycyrrhizin; ombitasvir; paritaprevir; ritonavir; ursodeoxycholic acid.