Clin Ther. 2015;37(11):2560–2571.

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

Jiuhong Zha, PhD1; Prajakta S. Badri, PhD1; Bifeng Ding, MS1; Naotaka Uchiyama, PhD2; Katia Alves, MD1; Lino Rodrigues-Jr,MD1; Rebecca Redman, MD1; Sandeep Dutta, PhD1; and Rajeev M. Menon, PhD1

1AbbVie Inc., North Chicago, Illinois; and 2AbbVie GK, Japan Development, Tokyo, Japan

 

Abstract

Purpose: The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for 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: Following 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 to 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

PMID: 26505529

 

Supplement

Approximately 1.5 to 2.0 million people in Japan and over 150 million people worldwide are chronically infected with hepatitis C virus (HCV).1-3  HCV genotype 1 is the most common genotype worldwide.4  In Japan, HCV subtype 1b is most prevalent.5  Individuals chronically infected with HCV are at risk of dying from liver cirrhosis and/or liver cancer.1

Ombitasvir and paritaprevir are antiviral drugs that have distinct and different mechanisms of action against HCV.  The 2D regimen of ombitasvir/paritaprevir/ritonavir (Viekirax) has been approved in Japan for the treatment of chronic HCV genotype 1 infection. This approval was supported by the GIFT-I study, a late-phase study in GT1b HCV infected Japanese patients without cirrhosis or with compensated cirrhosis.6

UDCA is a naturally-occurring bile acid found in small quantities in human plasma (blood).  Formulated UDCA is used for the improvement of liver function in HCV infection,7 for dissolving and preventing gallstones, and for the treatment of primary biliary cirrhosis, among other conditions.8-12  GCR is a glycosylated saponin found in the roots of the licorice plant.  GCR is used for the improvement of abnormal liver function in patients with chronic liver disease and for other treatment uses.7,13  UDCA and GCR are widely used in Japan. Because UDCA and GCR are metabolized or transported by some of the same enzymes and transporters as ombitasvir, paritaprevir and ritonavir, use of UDCA and GCR in HCV-infected patients being treated with the 2D regimen may cause drug interactions that affect plasma concentrations (exposures) of each other.

We conducted a study in non-HCV-infected, healthy Japanese subjects to evaluate potential interactions between the 2D regimen and UDCA or GCR to guide dosing recommendations for HCV-infected patients who choose to use hepatoprotective agents during treatment with the 2D regimen.

Two groups of healthy volunteers were included in the study: one group received UDCA alone or in combination with the 2D regimen, while the other group received GCR alone or in combination with the 2D regimen. Subjects received UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) alone for 2 days, the 2D regimen alone for 14 days, and UDCA or GCR plus the 2D regimen for 2 days.  Lower doses of UDCA and GCR were used in this study compared with those typically used in HCV-infected patients12,13 to account for potential interactions with the 2D regimen. All drugs were administered after a meal.  Blood samples were obtained at multiple time points to evaluate plasma concentrations (exposures) of each drug.

Results

Although UDCA and GCR have been shown to have metabolic and transporter profiles similar to those of the 2D regimen,14-17 coadministration of either UDCA or GCR with the 2D regimen for 2 days did not affect ombitasvir, paritaprevir, or ritonavir exposures (plasma concentrations) to a meaningful extent.  UDCA exposures were only slightly affected by the 2D regimen. Coadministering GCR with the 2D regimen had no effect on maximum plasma concentration of GCR, but resulted in an approximate 50% increase in GCR overall exposure (concentrations over 24 hours).  The underlying mechanism and clinical implications for this increase in GCR exposure are unknown; however, this increase in itself appears to be modest and GCR is not known to be a narrow therapeutic index drug.

This study showed that the 2D regimen had similar safety when used alone and when used with UDCA or GCR. Use of the 2D regimen with UDCA or GCR was well tolerated by the healthy subjects in this study and no new safety signals were identified.

Importance

The results of this study demonstrate that HCV patients should be able to continue using liver protective agents (UDCA or GCR) while concurrently treating their HCV infection with the 2D regimen of ombitasvir/paritaprevir/ritonavir without dose adjustment. Clinical monitoring of patients using GCR is recommended due to an approximate 50% increase in GCR overall exposure when coadministered with the 2D regimen.

 

Acknowledgments

This study was sponsored by AbbVie.  AbbVie contributed to the study design, research, and interpretation of data, and the writing, reviewing, and approving of the manuscript.  All authors are AbbVie employees and may hold AbbVie stock or stock options.

 

Contact:  Jiuhong Zha, PhD, AbbVie Inc., 1 North Waukegan Rd., Department R4PK, Bldg. AP31-3, North Chicago, IL 60064

E-mail: jiuhong.zha@abbvie.com

 

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