gth of glecaprevir is based on anhydrous glecaprevir. Glecaprevir is a white to off-white crystalline powder with a solubility of less than 0.1 to 0.3 mg/mL across a pH range of 2–7 at 37°C and is practically insoluble in water, but is sparingly soluble in ethanol. Glecaprevir has the following molecular structure:
glecaprevir
Pibrentasvir drug substance:
The chemical name of pibrentasvir is Methyl {(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate.
The molecular formula is C57H65F5N10O8 and the molecular weight for the drug substance is 1113.18 g/mol. Pibrentasvir is a white to off-white to light yellow crystalline powder with a solubility of less than 0.1 mg/mL across a pH range of 1–7 at 37°C and is practically insoluble in water, but is freely soluble in ethanol. Pibrentasvir has the following molecular structure:
pibrentasvir chem structure
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Mechanism of Action
MAVYRET is a fixed-dose combination of glecaprevir and pibrentasvir, which are direct-acting antiviral agents against the hepatitis C virus [see Microbiology (12.4)].
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of doses up to glecaprevir 600 mg (2 times the recommended dosage) with doses up to pibrentasvir 240 mg (2 times the recommended dosage) on QTc interval was eva luated in an active-controlled (moxifloxacin 400 mg) thorough QT study. At 20-fold of glecaprevir and 5-fold of pibrentasvir therapeutic concentrations, the glecaprevir and pibrentasvir combination does not prolong the QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics
The pharmacokinetic properties of the components of MAVYRET in healthy subjects are provided in TABLE 6. The steady-state pharmacokinetic parameters of glecaprevir and pibrentasvir in HCV-infected subjects without cirrhosis are provided in TABLE 7.
Table 6. Pharmacokinetic Properties of the Components of MAVYRET in Healthy Subjects
Glecaprevir Pibrentasvir
Absorption
Tmax (h)a 5.0 5.0
Effect of meal (relative to fasting)b ↑ 83-163% ↑ 40-53%
Distribution
% Bound to human plasma proteins 97.5 >99.9
Blood-to-plasma ratio 0.57 0.62
Elimination
t1/2 (h) 6 13
Metabolism secondary,
CYP3A None
Major route of excretion biliary-fecal biliary-fecal
% of dose excreted in urinec 0.7 0
% of dose excreted in fecesc 92.1 96.6
a. Median Tmax following single doses of glecaprevir and pibrentasvir in healthy subjects.
b. Mean systemic exposures with moderate to high fat meals.
c. Single dose administration of radiolabeled glecaprevir or pibrentasvir in mass balance studies.
Table 7. Steady-State Pharmacokinetic Parameters of Glecaprevir and Pibrentasvir Following Administration of MAVYRET in Non-Cirrhotic HCV-Infected Subjects
Pharmacokinetic Parameter Glecaprevirb Pibrentasvirc
Cmax (ng/mL)a 597 (114) 110 (49)
AUC24,ss (ng h/mL)a 4800 (122) 1430 (57)
a Geometric mean (%CV) of individual-estimated Cm |
