Glecaprevir/Pibrentasvir Unaffected by Acid-Reducing Drugs for Hepatitis C

MARCH 01, 2019
Kenneth Bender, PharmD, MA
A new analysis of multiple studies with glecaprevir/pibrentasvir (G/P; Mavyret) confirms that pan-genotypic efficacy for hepatitis C virus (HCV) is achieved regardless of whether patients are concurrently receiving gastric acid-reducing drugs.

This analysis of data from 9 phase 2 and 3 clinical trials assessing the efficacy and safety of G/P follows a phase 1 study that found absorption of glecaprevir—but not pibrentasvir—can be reduced by concurrent acid-reducing drugs, as glecaprevir solubility decreases with increased gastric pH. A subsequent analysis of exposure-efficacy relationships, however, found high rates of sustained virologic response (SVR) with G/P despite the drug interaction.

Steven Flamm MD, Professor of Medicine (Gastroenterology and Hepatology) and Surgery at Northwestern Feinberg School of Medicine, and colleagues suggested that the efficacy despite interaction indicates that glecaprevir plasma levels remain above therapeutic threshold, and that the unaffected pibrentasvir plasma levels are an independent predictor of sustained virologic response (SVR) with G/P treatment.

To further evaluate the clinical significance of the interaction and to confirm that efficacy is achieved despite it, the investigators conducted a retrospective analysis of 401 patients who had received acid reducing drugs during their participation in phase 2 and 3 trials of G/P for chronic HCV infection.

"This study assessing the efficacy and pharmacokinetics of G/P in the setting of concurrent acid-reducing agents (ARAs) for chronic HCV is an important one," Flamm told MD Magazine®. "Other commonly used anti-viral agents for treatment of chronic HCV have pH-related solubility issues that affect absorption and bioavailability of the agents that restrict usage in the setting of ARAs.”

ARAs present a challenge to these findings, though—they are commonly used medications, Flamm noted.

“Fortunately, phase 1 trials with G/P did not reveal a clinically relevant decrement in efficacy in patients with HCV, so ARAs were allowed in the phase 2/3 treatment program," he explained.

The combined population of the studies included 263 taking proton pump inhibitors (PPIs), 109 of whom were receiving high dose (greater than 20 mg omeprazole or equivalent). In addition, 84 patients were taking H2 histamine blockers and 54 received antacids. The investigators noted that, although patients who received at least 1 dose of an ARA were included in their analysis, most were using the agent throughout the course of treatment with G/P.

Flamm and colleagues found that the bioavailability of glecaprevir, but not pibrentasvir, was affected by concurrent acid reducing drugs, with a 41% decrease in plasma area under the curve (AUC) in patients receiving high dose PPI. This was consistent with the phase 1 study, in which there was a 29% reduction in glecaprevir AUC with 20 mg daily omeprazole, and 51% reduction in AUC with 40 mg daily omeprazole.

The investigators also reported that the high SVR rates did not statistically significantly differ between patients who were not on acid reducing drugs (97.5%) and those who were receiving them concurrent with G/P (97.0%).

"It should be noted that this is a retrospective analysis, and therefore the comparison was not prespecified," Flamm pointed out. "Yet, the subject number is large and offers reassurance that G/P is highly effective in the population of patients that require ARAs during the course of antiviral therapy for HCV."

The study, “Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir with Concurrent Use of Acid-Reducing Agents in Patients with Chronic HCV Infection,” was published online in Clinical Gastroenterology and Hepatology.

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