Glecaprevir + Pibrentasvir

Approved indications

• Chronic Hepatitis C Virus (HCV) infection: Treatment of adults and pediatric patients (≥12 years and weighing ≥45 kg) with HCV genotypes 1–6.
• Compensated liver disease: Effective in patients with chronic HCV infection with or without compensated cirrhosis (Child-Pugh A).
• Treatment-naïve and treatment-experienced patients: Includes patients with prior exposure to interferon-based therapy or direct-acting antivirals (excluding NS5A inhibitor failures, depending on genotype and regimen).

Off-label / clinically accepted uses

• Salvage therapy in select patients with prior treatment failure using alternative regimens.
• Investigational use in HCV/HIV co-infected patients in combination with antiretroviral therapy.

Adults

• Standard dose: Fixed-dose combination of Glecaprevir 300 mg + Pibrentasvir 120 mg orally once daily.
• Route: Oral; tablets should be taken with food to improve absorption.
• Duration:
• 8 weeks: For treatment-naïve patients without cirrhosis or with compensated cirrhosis, depending on genotype.
• 12 weeks: For patients with previous treatment experience or with compensated cirrhosis.

Dose adjustments

• Renal impairment: No adjustment needed, including severe impairment or hemodialysis.
• Hepatic impairment:
• Child-Pugh A: No adjustment required.
• Child-Pugh B or C: contraindicated due to increased risk of liver toxicity.

Pediatrics

• Approved for patients ≥12 years and ≥45 kg; standard adult dosing applies.

Elderly

• No specific adjustment; monitor for comorbidities and concomitant medications.

Glecaprevir is a NS3/4A protease inhibitor, preventing HCV polyprotein cleavage and viral replication. Pibrentasvir is a NS5A inhibitor, blocking viral RNA replication and virion assembly. The combination targets multiple steps in the HCV lifecycle, leading to potent antiviral activity and a high likelihood of achieving sustained virologic response (SVR). By simultaneously inhibiting viral protease and NS5A, resistance development is minimized.

• Absorption: Peak plasma concentrations occur 3–5 hours post-dose; absorption enhanced with food.
• Bioavailability: Oral absorption adequate with food; tablets should not be taken on an empty stomach.
• Distribution: Highly protein-bound (>97%); extensive tissue distribution.
• Metabolism:
• Glecaprevir: Primarily metabolized by CYP3A4.
• Pibrentasvir: Minimally metabolized, mainly via oxidation and amide hydrolysis.
• Elimination:
• Glecaprevir: Mainly fecal (~92%).
• Pibrentasvir: Primarily fecal (~98%).
• Half-life:
• Glecaprevir: ~6 hours
• Pibrentasvir: ~23 hours
• Steady state: Achieved within 5–7 days of daily dosing.

• Pregnancy: No well-controlled studies in humans; use only if potential benefit justifies risk. Animal studies show no teratogenicity at therapeutic exposures.
• Breastfeeding: Unknown if excreted in human milk; breastfeeding not recommended during treatment.
• Caution: Women of childbearing potential should use effective contraception during treatment.

• Primary class: Antiviral agent
• Subclass: Direct-acting antiviral (DAA) combination — NS3/4A protease inhibitor + NS5A inhibitor

• Known hypersensitivity to Glecaprevir, Pibrentasvir, or any excipients.
• Moderate-to-severe hepatic impairment (Child-Pugh B or C).
• Concomitant use with strong CYP3A inducers (e.g., rifampin, carbamazepine) or P-gp inducers due to reduced efficacy.

• Hepatic monitoring: Risk of elevated liver enzymes; monitor LFTs during therapy.
• HCV/HIV co-infection: Monitor for potential drug interactions with antiretroviral therapy.
• Reactivation of Hepatitis B: Screen all patients before initiating therapy; monitor HBsAg-positive patients.
• Renal impairment: Safe, but monitor for other comorbidities.
• Drug interactions: Check all concomitant medications for CYP3A or P-gp interactions.

Common

• Fatigue, headache
• Nausea, diarrhea
• Pruritus, rash

Serious / rare

• Severe hepatic adverse events (rare, mostly in patients with unrecognized hepatic impairment)
• Anemia
• Hyperbilirubinemia

Onset: Side effects usually appear within the first few weeks of therapy; most are mild and self-limiting.

• CYP3A inducers (e.g., rifampin, St. John’s wort): Reduce drug levels; avoid co-administration.
• P-gp inducers: May reduce exposure; avoid or adjust regimen.
• Statins: Monitor for increased statin exposure; risk of myopathy.
• Acid-reducing agents: Minimal effect, but separation from antacids by 4 hours recommended for optimal absorption.

• 2024 updates: Glecaprevir + Pibrentasvir is now recommended for all HCV genotypes 1–6, including patients with compensated cirrhosis.
• Shortened duration (8 weeks): Approved for treatment-naïve patients without cirrhosis, improving adherence and reducing cost.
• Revised safety guidance: Enhanced monitoring for HBV reactivation and liver function is now emphasized in clinical guidelines.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture, heat, and light.
• Keep in original container with tightly closed cap.
• Do not freeze.
• Keep out of reach of children.