Grazoprevir Hydrate

China [CN]

I. Basic Information

Generic Name: Grazoprevir Hydrate

Development Code: MK-5172

CAS Number: 1350462-55-3

Molecular Formula: C₃₈H₅₂N₆O₁₀S

Molecular Weight: 784.92

Original Developer: Merck Sharp & Dohme

Clinical Form: Fixed-dose combination (GZR 100 mg + EBR 50 mg/tablet)

II. Mechanism of Action

Target: HCV NS3/4A serine protease (a key enzyme essential for viral replication)

Mechanism: Potently inhibits NS3/4A protease activity, blocking the cleavage and maturation of HCV polyproteins, preventing viral replication and assembly.

Pangenotypic Activity: Potent inhibition against HCV genotypes 1–6, Ki values:

GT1a/1b: 0.01 nM

GT2a: 0.08 nM

GT2b: 0.15 nM

GT3a: 0.90 nM

Resistance Profile: Maintains high activity against common NS3 resistance mutations (e.g., D168, A156), high resistance barrier.

Combination Synergy: Used in combination with Elbasvir (EBR, an NS5A inhibitor), dual-target blockade significantly improves cure rates and reduces the risk of resistance.

III. Core Indications (GZR/EBR combination, Zepatier®)

Adult Chronic Hepatitis C (CHC):

Genotype 1 (GT1): Without cirrhosis or with compensated cirrhosis (Child-Pugh A), 12-week treatment course, SVR₁₂ ≈ 95%–99%

Genotype 4 (GT4): Without cirrhosis, 12-week treatment course

Previously treated patients: GT1, previous treatment failure with NS5A inhibitors, 16-week treatment course Weekly Treatment Regimen

IV. Pharmacokinetics (GZR)

Absorption: Well absorbed orally; bioavailability increased with food.

Protein Binding Rate: >99%

Metabolism: Primarily metabolized by CYP3A

Half-life: Approximately 31 hours (once daily administration)

Excretion: 80% in feces, 10% in urine; no dose adjustment needed for mild to moderate renal impairment.

V. Adverse Reactions (Combination Therapy)

Common (≥5%): Fatigue, headache, nausea, diarrhea, insomnia

Serious: Elevated liver enzymes (ALT/AST), elevated bilirubin; contraindicated in decompensated cirrhosis.

Contraindications: Child-Pugh B/C cirrhosis, concomitant use with rifampicin, allergy.

VI. Drug Interactions (Key)

GZR/EBR are: P-gp, BCRP, OATP1B1/3 inhibitors; CYP3A inhibitors

Contraindicated for concomitant use: Rifampicin (significantly reduces GZR/EBR exposure)

Use with caution/monitor: Statins, calcium channel blockers, immunosuppressants, warfarin (may increase blood drug concentration)