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VIEKIRA XR(dasabuvir, ombitasvir, paritaprevir, and ritonavir)extended-release tablets(十八)
, Ritonavir Film-Coated Bilayer Tablets
Dasabuvir, ombitasvir, paritaprevir, and ritonavir film-coated bilayer tablets consist of an extended release (ER) layer and an immediate release (IR) layer. The ER layer contains 200 mg dasabuvir (equivalent to 216.2 mg of dasabuvir sodium monohydrate). The ER layer of the tablet also contains copovidone, K value 28, hypromellose 2208, 17,700 (mPa*s), colloidal silicon dioxide/colloidal anhydrous silica and magnesium stearate. The IR layer contains 8.33 mg ombitasvir, 50 mg paritaprevir and 33.33 mg ritonavir. Strength of ombitasvir and paritaprevir in the drug product are expressed on the anhydrous basis. The IR layer of the tablet also contains copovidone, K value 28, vitamin E polyethylene glycol succinate, propylene glycol monolaurate, sorbitan monolaurate, colloidal silicon dioxide/colloidal anhydrous silica. The tablet coating contains hypromellose (6 mPa*s), hypromellose (15 mPa*s), polyethylene glycol 400, hydroxypropyl cellulose, polysorbate 80, polyethylene glycol 3350/macrogol 4000, talc, titanium dioxide, colloidal silicon dioxide/colloidal anhydrous silica and iron oxide yellow.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
VIEKIRA XR combines three direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology (12.4)].
Ritonavir is not active against HCV. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of a combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir on QTc interval was eva luated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects. At concentrations approximately 6, 1.8 and 2 times the therapeutic concentrations of paritaprevir, ombitasvir, and dasabuvir, the combination did not prolong QTc to any clinically relevant extent.
12.3 Pharmacokinetics
Dasabuvir, ombitasvir, paritaprevir, and ritonavir film-coated bilayer tablets consist of an extended-release (ER) layer of dasabuvir and an immediate-release (IR) layer of ombitasvir, paritaprevir and ritonavir.
The pharmacokinetic properties of the components of VIEKIRA XR are provided in TABLE 6.
Table 6. Pharmacokinetic Properties of the Components of VIEKIRA XR
Ombitasvir Paritaprevir Ritonavir Dasabuvir
Absorption
Tmax (hr) median values 5 5 4 8
Absolute
bioavailability (%) 48 53 NA 70
Effect of high fat meal
relative to fastinga,b 1.96
(1.83-2.15) 4.60
(3.8-5.57) 2.13
(1.86-2.43) 5.92
(5.06-6.92)
Accumulationc 0.90- to
1.03-fold 1.5- to 2-fold 0.96-fold
Distribution
% Bound to human plasma proteins 99.9 97-98.6 >99 >99.5
Blood-to-plasma ratio 0.49 0.7 0.6 0.7
Volume of distribution
at steady state (Vss) (L) 173 103 21.5d 149
Metabolism
Metabolism amide hydrolysis
followed by
oxidative
metabolism CYP3A4 (major),
CYP3A5 CYP3A (major),
CYP2D6 CYP2C8 (major),
CYP3A
Eliminatione
Major route of eliminat |
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