Viekira XR Tablets - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Viekira XR Tablets - Scientific Information

Manufacture: AbbVie
Country: United States
Condition: Hepatitis C
Class: Antiviral combinations
Form: Tablets
Ingredients: Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir, Copovidone, K Value 28, Hypromellose 2208, 17,700 (mpa*s), Colloidal Silicon Dioxide/colloidal Anhydrous Silica, Magnesium Stearate, Vitamin E Polyethylene Glycol Succinate, Propylene Glycol Monolaurate, Sorbitan Monolaurate, Colloidal Silicon Dioxide/colloidal Anhydrous Silica, 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, Iron Oxide Yellow

Description

VIEKIRA XR fixed dose combination, extended-release tablet includes a hepatitis C virus non-nucleoside NS5B palm polymerase inhibitor (dasabuvir), a hepatitis C virus NS5A inhibitor (ombitasvir), a hepatitis C virus NS3/4A protease inhibitor (paritaprevir), and a CYP3A inhibitor (ritonavir) that inhibits CYP3A mediated metabolism of paritaprevir, thereby providing increased plasma concentration of paritaprevir. The tablets are for oral administration.

Dasabuvir

The chemical name of dasabuvir is Sodium 3-(3-tert -butyl-4-methoxy-5-{6-[(methylsulfonyl)amino]naphthalene-2-yl}phenyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ide hydrate (1:1:1). The molecular formula is C26 H26 N3 O5 S•Na•H2 O (salt, hydrate) and the molecular weight of the drug substance is 533.57 (salt, hydrate). The drug substance is white to pale yellow to pink powder, slightly soluble in water and very slightly soluble in methanol and isopropyl alcohol. Dasabuvir has the following molecular structure:

Ombitasvir

The chemical name of ombitasvir is Dimethyl ([(2S ,5S)-1-(4-tert -butylphenyl) pyrrolidine-2,5-diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2-diyl]})biscarbamate hydrate. The molecular formula is C50 H67 N7 O8 •4.5H2 O (hydrate) and the molecular weight for the drug substance is 975.20 (hydrate). The drug substance is white to light yellow to light pink powder, and is practically insoluble in aqueous buffers but is soluble in ethanol. Ombitasvir has the following molecular structure:

Paritaprevir

The chemical name of paritaprevir is (2R,6S,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-{[(5-methylpyrazin-2-yl)carbonyl]amino}-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e ]pyrrolo[1,2-a ][1,4] diazacyclopentadecine-14a(5H)-carboxamide dihydrate. The molecular formula is C40 H43 N7 O7 S•2H2 O (dihydrate) and the molecular weight for the drug substance is 801.91 (dihydrate). The drug substance is white to off-white powder with very low water solubility. Paritaprevir has the following molecular structure:

Ritonavir

The chemical name of ritonavir is [5S-(5R*,8R*,10R*,11R*)]10-Hydroxy-2-methyl-5-(1-methyethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester. The molecular formula is C37 H48 N6 O5 S2 and the molecular weight for the drug substance is 720.95. The drug substance is white to off white to light tan powder practically insoluble in water and freely soluble in methanol and ethanol. Ritonavir has the following molecular structure:

Dasabuvir, Ombitasvir, Paritaprevir, 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.

Clinical Pharmacology

Mechanism of Action

VIEKIRA XR combines three direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action [see Microbiology].

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).

Pharmacodynamics

Cardiac Electrophysiology

The effect of a combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir on QTc interval was evaluated 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.

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 1.

Table 1. 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 elimination biliary excretion metabolism metabolism metabolism
t1/2 (hr)f 21-25 5.5 4 5.5-6
% of dose excreted in fecesg 90.2 88 86.4 94.4
% of dose excreted unchanged in fecesg 87.8 1.1 33.8 26.2
% of dose excreted in urineg 1.91 8.8 11.3 ~ 2
% of dose excreted unchanged in urineg 0.03 0.05 3.5 0.03
NA - data not available
a. High fat meal of 753 Kcal; 55.3% calories from fat, 27.8% calories from carbohydrates, and 16.9% calories from protein.
b.Similar results are expected for ombitasvir, paritaprevir and dasabuvir under moderate fat meal conditions.
c. Steady state exposures are achieved after approximately 12 days of dosing.
d.It is apparent volume of distribution (V/F) for ritonavir.
e. Ombitasvir, paritaprevir, ritonavir, and dasabuvir do not inhibit organic anion transporter (OAT1) in vivo and based on in vitro data, are not expected to inhibit organic cation transporter (OCT2), organic anion transporter (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.
f. t1/2 values refer to the mean elimination half-life.
g. Dosing in mass balance studies: single dose administration of [14 C] ombitasvir; single dose administration of [14 C] paritaprevir co-dosed with 100 mg ritonavir; single dose administration of [14 C] dasabuvir.

Specific Populations

There are no clinically relevant changes in the pharmacokinetics of the components of VIEKIRA XR in relation to sex, race/ethnicity, or geriatric age [see Use in Specific Populations]. The pharmacokinetics of VIEKIRA XR in pediatric patients less than 18 years of age have not been established [see Use in Specific Populations].

Hepatic Impairment

The single dose pharmacokinetics of the combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir were evaluated in non-HCV infected subjects with mild hepatic impairment (Child-Pugh Category A; score of 5-6), moderate hepatic impairment (Child-Pugh Category B, score of 7-9) and severe hepatic impairment (Child-Pugh Category C, score of 10-15).

Relative to subjects with normal hepatic function, dasabuvir AUC values increased by 17%, and ombitasvir, paritaprevir and ritonavir AUC values decreased by 8%, 29% and 34%, respectively, in subjects with mild hepatic impairment.

Relative to subjects with normal hepatic function, dasabuvir, ombitasvir, and ritonavir AUC values decreased by 16%, 30%, and 30% respectively, and paritaprevir AUC values increased by 62% in subjects with moderate hepatic impairment.

Relative to subjects with normal hepatic function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 325%, 945%, and 13%, respectively, and ombitasvir AUC values decreased by 54% in subjects with severe hepatic impairment.

Renal Impairment

The single dose pharmacokinetics of the combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir were evaluated in non-HCV infected subjects with mild (CLcr : 60 to 89 mL/min), moderate (CLcr : 30 to 59 mL/min), and severe (CLcr : 15 to 29 mL/min) renal impairment.

Pharmacokinetic data are not available on the use of VIEKIRA XR in non-HCV infected subjects with End Stage Renal Disease (ESRD).

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 21%, 19%, and 42% respectively, while ombitasvir AUC values were unchanged in subjects with mild renal impairment.

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 37%, 33%, and 80% respectively, while ombitasvir AUC values were unchanged in subjects with moderate renal impairment.

Relative to subjects with normal renal function, dasabuvir, paritaprevir, and ritonavir AUC values increased by 50%, 45%, and 114% respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment [see Use in Specific Populations].

Drug Interaction Studies

See also Contraindications, Warnings and Precautions, Drug Interactions

All drug-drug interaction trials were conducted with VIEKIRA PAK. The effects of some drugs discussed in Table 5 on the exposures of dasabuvir, ombitasvir, paritaprevir, and ritonavir are shown in Table 2. For information regarding clinical recommendations, see Drug Interactions.

Table 2. Drug Interactions: Change in Pharmacokinetic Parameters of Dasabuvir, Ombitasvir, Paritaprevir, and Ritonavir in the Presence of Co-administered Drug
Co-administered Drug Dose of Co-administered Drug (mg) n DAA Ratio (with/without co-administered drug) of DAA Pharmacokinetic Parameters (90% CI); No Effect = 1.00
  Cmax AUC Cmin
Alprazolam 0.5 single dose 12 dasabuvir 0.93 (0.83, 1.04) 0.98 (0.87, 1.11) 1.00 (0.87, 1.15)
ombitasvir 0.98 (0.93, 1.04) 1.00 (0.96, 1.04) 0.98 (0.93, 1.04)
paritaprevir 0.91 (0.64, 1.31) 0.96 (0.73, 1.27) 1.12 (1.02, 1.23)
ritonavir 0.92 (0.84, 1.02) 0.96 (0.89, 1.03) 1.01 (0.94, 1.09)
Amlodipine 5 single dose 14 dasabuvir 1.05 (0.97, 1.14) 1.01 (0.96, 1.06) 0.95 (0.89, 1.01)
ombitasvir 1.00 (0.95, 1.06) 1.00 (0.97, 1.04) 1.00 (0.97, 1.04)
paritaprevir 0.77 (0.64, 0.94) 0.78 (0.68, 0.88) 0.88 (0.80, 0.95)
ritonavir 0.96 (0.87, 1.06) 0.93 (0.89, 0.98) 0.95 (0.89, 1.01)
Atazanavir/ritonavira Atazanavir 300 and ritonavir 100 once daily in the evening 11 dasabuvir 0.81 (0.73, 0.91) 0.81 (0.71, 0.92) 0.80 (0.65, 0.98)
ombitasvir 0.83 (0.72, 0.96) 0.90 (0.78, 1.02) 1.00 (0.89, 1.13)
paritaprevir 2.19 (1.61, 2.98) 3.16 (2.40, 4.17) 11.95 (8.94, 15.98)
ritonavir 1.60 (1.38, 1.86) 3.18 (2.74, 3.69) 24.65 (18.64, 32.60)
Carbamazepine 200 once daily followed by 200 twice daily 12 dasabuvir 0.45 (0.41, 0.50) 0.30 (0.28, 0.33) NA
ombitasvir 0.69 (0.61, 0.78) 0.69 (0.64, 0.74) NA
paritaprevir 0.34 (0.25, 0.48) 0.30 (0.23, 0.38) NA
ritonavir 0.17 (0.12, 0.24) 0.13 (0.09, 0.17) NA
Carisoprodol 250 single dose 14 dasabuvir 0.96 (0.91, 1.01) 1.02 (0.97, 1.07) 1.00 (0.92, 1.10)
ombitasvir 0.98 (0.92, 1.04) 0.95 (0.92, 0.97) 0.96 (0.92, 0.99)
paritaprevir 0.88 (0.75, 1.03) 0.96 (0.85, 1.08) 1.14 (1.02, 1.27)
ritonavir 0.94 (0.87, 1.02) 0.94 (0.88, 0.99) 0.95 (0.89, 1.03)
Cyclobenzaprine 5 single dose 14 dasabuvir 0.98 (0.90, 1.07) 1.01 (0.96, 1.06) 1.13 (1.07, 1.18)
ombitasvir 0.98 (0.92, 1.04) 1.00 (0.97, 1.03) 1.01 (0.98, 1.04)
paritaprevir 1.14 (0.99, 1.32) 1.13 (1.00, 1.28) 1.13 (1.01, 1.25)
ritonavir 0.93 (0.87, 0.99) 1.00 (0.95, 1.06) 1.13 (1.05, 1.21)
Cyclosporine 30 single doseb 10 dasabuvir 0.66 (0.58, 0.75) 0.70 (0.65, 0.76) 0.76 (0.71, 0.82)
ombitasvir 0.99 (0.92, 1.07) 1.08 (1.05, 1.11) 1.15 (1.08, 1.23)
paritaprevir 1.44 (1.16, 1.78) 1.72 (1.49, 1.99) 1.85 (1.58, 2.18)
ritonavir 0.90 (0.78, 1.04) 1.11 (1.04, 1.19) 1.49 (1.28, 1.74)
Darunavirc 800 once daily 9 dasabuvir 1.10 (0.88, 1.37) 0.94 (0.78, 1.14) 0.90 (0.76, 1.06)
ombitasvir 0.86 (0.77, 0.95) 0.86 (0.79, 0.94) 0.87 (0.82, 0.92)
paritaprevir 1.54 (1.14, 2.09) 1.29 (1.04, 1.61) 1.30 (1.09, 1.54)
ritonavir 0.84 (0.72, 0.98) 0.85 (0.78, 0.93) 1.07 (0.93, 1.23)
Darunavir/ritonavird Darunavir 600 twice daily and ritonavir 100 once daily in the evening 7 dasabuvir 0.84 (0.67, 1.05) 0.73 (0.62, 0.86) 0.54 (0.49, 0.61)
ombitasvir 0.76 (0.65, 0.88) 0.73 (0.66, 0.80) 0.73 (0.64, 0.83)
paritaprevir 0.70 (0.43, 1.12) 0.59 (0.44, 0.79) 0.83 (0.69, 1.01)
ritonavir 1.61 (1.30, 2.00) 1.28 (1.12, 1.45) 0.88 (0.79, 0.99)
Darunavir/ritonavire Darunavir 800 and ritonavir 100 once daily in the evening 12 dasabuvir 0.75 (0.64, 0.88) 0.72 (0.64, 0.82) 0.65 (0.58, 0.72)
ombitasvir 0.87 (0.82, 0.93) 0.87 (0.81, 0.93) 0.87 (0.80, 0.95)
paritaprevir 0.70 (0.50, 0.99) 0.81 (0.60, 1.09) 1.59 (1.23, 2.05)
ritonavir 1.19 (1.06, 1.33) 1.70 (1.54, 1.88) 14.15 (11.66, 17.18)
Diazepam 2 single dose 13 dasabuvir 1.05 (0.98, 1.13) 1.01 (0.94, 1.08) 1.05 (0.98, 1.12)
ombitasvir 1.00 (0.93, 1.08) 0.98 (0.93, 1.03) 0.93 (0.88, 0.98)
paritaprevir 0.95 (0.77, 1.18) 0.91 (0.78, 1.07) 0.92 (0.82, 1.03)
ritonavir 1.10 (1.02, 1.19) 1.06 (0.98, 1.14) 0.98 (0.92, 1.03)
Ethinyl estradiol/Norgestimate Ethinyl estradiol 0.035 and Norgestimate 0.25 once daily 7f dasabuvir 0.51 (0.22, 1.18) 0.48 (0.23, 1.02) 0.53 (0.30, 0.95)
ombitasvir 1.05 (0.81, 1.35) 0.97 (0.81, 1.15) 1.00 (0.88, 1.12)
paritaprevir 0.70 (0.40, 1.21) 0.66 (0.42, 1.04) 0.87 (0.67, 1.14)
ritonavir 0.80 (0.53, 1.21) 0.71 (0.54, 0.94) 0.79 (0.68, 0.93)
Furosemide 20 single dose 12 dasabuvir 1.12 (0.96, 1.31) 1.09 (0.96, 1.23) 1.06 (0.98, 1.14)
ombitasvir 1.14 (1.03, 1.26) 1.07 (1.01, 1.12) 1.12 (1.08, 1.16)
paritaprevir 0.93 (0.63, 1.36) 0.92 (0.70, 1.21) 1.26 (1.16, 1.38)
ritonavir 1.10 (0.96, 1.27) 1.04 (0.92, 1.18) 1.07 (0.99, 1.17)
Gemfibrozilg 600 twice daily 11 dasabuvir 2.01 (1.71, 2.38) 11.25 (9.05, 13.99) NA
ombitasvir NA NA NA
paritaprevir 1.21 (0.94, 1.57) 1.38 (1.18, 1.61) NA
ritonavir 0.84 (0.69, 1.03) 0.90 (0.78, 1.04) NA
Hydrocodone/Acetaminophen 5/300 single dose 15 dasabuvir 1.13 (1.01, 1.26) 1.12 (1.05, 1.19) 1.16 (1.08, 1.25)
ombitasvir 1.01 (0.93, 1.10) 0.97 (0.93, 1.02) 0.93 (0.90, 0.97)
paritaprevir 1.01 (0.80, 1.27) 1.03 (0.89, 1.18) 1.10 (0.97, 1.26)
ritonavir 1.01 (0.90, 1.13) 1.03 (0.96, 1.09) 1.01 (0.93, 1.10)
Ketoconazole 400 once daily 12 dasabuvir 1.16 (1.03, 1.32) 1.42 (1.26, 1.59) NA
ombitasvir 0.98 (0.90, 1.06) 1.17 (1.11, 1.24) NA
paritaprevir 1.37 (1.11, 1.69) 1.98 (1.63, 2.42) NA
ritonavir 1.27 (1.04, 1.56) 1.57 (1.36, 1.81) NA
Lopinavir/ritonavir 400/100 twice daily 6 dasabuvir 0.99 (0.75, 1.31) 0.93 (0.75, 1.15) 0.68 (0.57, 0.80)
ombitasvir 1.14 (1.01, 1.28) 1.17 (1.07, 1.28) 1.24 (1.14, 1.34)
paritaprevir 2.04 (1.30, 3.20) 2.17 (1.63, 2.89) 2.36 (1.00, 5.55)
ritonavir 1.55 (1.16, 2.09) 2.05 (1.49, 2.81) 5.25 (3.33, 8.28)
Lopinavir/ritonavirh 800/200 once daily 12 dasabuvir 0.56(0.47, 0.66) 0.54 (0.46, 0.65) 0.47 (0.39, 0.58)
ombitasvir 0.87 (0.83, 0.92) 0.97 (0.94, 1.02) 1.11 (1.06, 1.16)
paritaprevir 0.99 (0.79, 1.25) 1.87 (1.40, 2.52) 8.23 (5.18, 13.07)
ritonavir 1.57 (1.34, 1.83) 2.62 (2.32, 2.97) 19.46 (15.93, 23.77)
Omeprazole 40 once daily 11 dasabuvir 1.13 (1.03, 1.25) 1.08 (0.98, 1.20) 1.05 (0.93, 1.19)
ombitasvir 1.02 (0.95, 1.09) 1.05 (0.98, 1.12) 1.04 (0.98, 1.11)
paritaprevir 1.19(1.04, 1.36) 1.18 (1.03, 1.37) 0.92 (0.76, 1.12)
ritonavir 1.04 (0.96, 1.12) 1.02 (0.97, 1.08) 0.97 (0.89, 1.05)
Pravastatin 10 once daily 12 dasabuvir 1.00 (0.87, 1.14) 0.96 (0.85, 1.09) 1.03 (0.91, 1.15)
ombitasvir 0.95 (0.89, 1.02) 0.94 (0.89, 0.99) 0.94 (0.89, 0.99)
paritaprevir 0.96 (0.69, 1.32) 1.13 (0.92, 1.38) 1.39 (1.21, 1.59)
ritonavir 0.89 (0.73, 1.09) 0.95 (0.86, 1.05) 1.08 (0.98, 1.19)
Rilpivirine 25 once daily (morning)i 10 dasabuvir 1.18 (1.02, 1.37) 1.17 (0.99, 1.38) 1.10 (0.89, 1.37)
ombitasvir 1.11 (1.02, 1.20) 1.09 (1.04, 1.14) 1.05 (1.01, 1.08)
paritaprevir 1.30 (0.94, 1.81) 1.23 (0.93, 1.64) 0.95 (0.84, 1.07)
ritonavir 1.10 (0.98, 1.24) 1.08 (0.93, 1.27) 0.97 (0.91, 1.04)
Rosuvastatin 5 once daily 11 dasabuvir 1.07 (0.92, 1.24) 1.08 (0.92, 1.26) 1.15 (1.05, 1.25)
ombitasvir 0.92 (0.82, 1.04) 0.89 (0.83, 0.95) 0.88 (0.83, 0.94)
paritaprevir 1.59 (1.13, 2.23) 1.52 (1.23, 1.90) 1.43 (1.22, 1.68)
ritonavir 0.98 (0.84, 1.15) 1.02 (0.93, 1.12) 1.00 (0.90, 1.12)
Tacrolimus 5 once daily 11 dasabuvir 0.85 (0.73, 0.98) 0.90 (0.80, 1.02) 1.01 (0.91, 1.11)
ombitasvir 0.93 (0.88, 0.99) 0.94 (0.89, 0.98) 0.94 (0.91, 0.96)
paritaprevir 0.57 (0.42, 0.78) 0.66 (0.54, 0.81) 0.73 (0.66, 0.80)
ritonavir 0.76 (0.63, 0.91) 0.87 (0.79, 0.97) 1.03 (0.89, 1.19)

a. Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR.
b. 30 mg cyclosporine was administered with the components of VIEKIRA XR in the test arm and 100 mg cyclosporine was administered in the reference arm without the components of VIEKIRA XR.
c. Darunavir administered with the components of VIEKIRA XR in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.
d. Darunavir administered with the components of VIEKIRA XR in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening.
e. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after the morning dose of the components of VIEKIRA XR compared to darunavir administered with 100 mg ritonavir in the evening.
f. N=3 for dasabuvir.
g. Study was conducted with paritaprevir, ritonavir and dasabuvir.
h. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR.
i. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval
Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg.
Dasabuvir was dosed twice daily and ombitasvir, paritaprevir and ritonavir were dosed once daily in all the above studies except studies with gemfibrozil, ketoconazole and carbamazepine that used single doses.

Table 3 summarizes the effects of dasabuvir, ombitasvir, paritaprevir, and ritonavir on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Drug Interactions.

Table 3. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIEKIRA XR
Co-administered Drug Dose of Co-administered Drug (mg) n Ratio (with/without the Components of VIEKIRA XR) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
  Cmax AUC Cmin
Alprazolam 0.5 single dose 12 1.09 (1.03, 1.15) 1.34 (1.15, 1.55) NA
Amlodipine 5 single dose 14 1.26 (1.11, 1.44) 2.57 (2.31, 2.86) NA
Atazanavir/ritonavira Atazanavir 300 and ritonavir 100 once daily in the evening 12 1.02 (0.92, 1.13)b 1.19 (1.11, 1.28)b 1.68 (1.44, 1.95)b
Buprenorphine Buprenorphine: 4 to 24 once daily and Naloxone 1 to 6 once daily 10 2.18 (1.78, 2.68)c 2.07 (1.78, 2.40)c 3.12 (2.29, 4.27)c
Norbuprenorphine 2.07 (1.42, 3.01)c 1.84 (1.30, 2.60)c 2.10 (1.49, 2.97)c
Naloxone 1.18 (0.81, 1.73) 1.28 (0.92, 1.79)c NA
Carbamazepine 200 once daily followed by 200 twice daily 12 1.10 (1.07, 1.14) 1.17 (1.13, 1.22) 1.35 (1.27, 1.45)
Carbamazepine’s metabolite, carbamazepine-10,11-epoxide (CBZE) 0.84 (0.82, 0.87) 0.75 (0.73, 0.77) 0.57 (0.54, 0.61)
Carisoprodol 250 single dose 14 0.54 (0.47, 0.63) 0.62 (0.55, 0.70) NA
Carisoprodol's metabolite, mepobramate 1.17 (1.10, 1.25) 1.09 (1.03, 1.16) NA
Cyclobenzaprine 5 single dose 14 0.68 (0.61, 0.75) 0.60 (0.53, 0.68) NA
Cyclobenzaprine's metabolite, norcyclobenzaprine 1.03 (0.87, 1.23) 0.74 (0.64, 0.85) NA
Cyclosporine 30 single dosed 10 1.01 (0.85, 1.20)c 5.82 (4.73, 7.14)c 15.80 (13.81, 18.09)c
Darunavire 800 once daily 8 0.92 (0.87, 0.98)b 0.76 (0.71, 0.82)b 0.52 (0.47, 0.58)b
Darunavir/ritonavirf Darunavir 600 twice daily and ritonavir 100 once daily in the evening 7 0.87 (0.79, 0.96)b 0.80 (0.74, 0.86)b 0.57 (0.48, 0.67)b
Darunavir/ritonavirg Darunavir 800 and ritonavir 100 once daily in the evening 10 0.79 (0.70, 0.90)b 1.34 (1.25, 1.43)b 0.54 (0.48, 0.62)b
Diazepam 2 single dose 13 1.18 (1.07, 1.30) 0.78 (0.73, 0.82) NA
Diazepam's metabolite, nordiazepam 1.10 (1.03, 1.19) 0.56 (0.45, 0.70) NA
Ethinyl Estradiol Ethinyl estradiol 0.035 and Norgestimate 0.25 once daily 8 1.16 (0.90, 1.50) 1.06 (0.96, 1.17) 1.12 (0.94, 1.33)
Norelgestromin 9 2.01 (1.77, 2.29) 2.60 (2.30, 2.95) 3.11 (2.51, 3.85)
Norgestrel 9 2.26 (1.91, 2.67) 2.54 (2.09, 3.09) 2.93 (2.39, 3.57)
Furosemide 20 single dose 12 1.42 (1.17, 1.72) 1.08 (1.00, 1.17) NA
Hydrocodone 5 single dose 15 1.27 (1.14, 1.40) 1.90 (1.72, 2.10) NA
Ketoconazole 400 once daily 12 1.15 (1.09, 1.21) 2.17 (2.05, 2.29) NA
Lopinavir/ritonavir 400/100 twice daily 6 0.87 (0.76, 0.99)b 0.94 (0.81, 1.10)b 1.15 (0.93, 1.42)b
Lopinavir/ritonavirh 800/200 once daily 12 0.86 (0.80, 0.93)b 0.94 (0.87, 1.01)b 3.18 (2.49, 4.06)b
Omeprazole 40 once daily 11 0.62 (0.48, 0.80) 0.62 (0.51, 0.75) NA
Pravastatin 10 once daily 12 1.37 (1.11, 1.69) 1.82 (1.60, 2.08) NA
Rilpivirine 25 once daily (morning)i 8 2.55 (2.08, 3.12) 3.25 (2.80, 3.77) 3.62 (3.12, 4.21)
Rosuvastatin 5 once daily 11 7.13 (5.11, 9.96) 2.59 (2.09, 3.21) 0.59 (0.51, 0.69)
Tacrolimus 2 single dose 12 3.99 (3.21, 4.97)c 57.13 (45.53, 71.69)c 16.56 (12.97, 21.16)c

a. Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR.
b.Atazanavir or darunavir or lopinavir parameters are reported.
c. Dose normalized parameters reported.
d.30 mg cyclosporine was administered with the components of VIEKIRA XR in the test arm and 100 mg cyclosporine was administered in the reference arm without the components of VIEKIRA XR.
e. Darunavir administered with the components of VIEKIRA XR in the morning was compared to darunavir administered with 100 mg ritonavir in the morning.
f. Darunavir administered with the components of VIEKIRA XR in the morning and with 100 mg ritonavir in the evening was compared to darunavir administered with 100 mg ritonavir in the morning and evening.
g.Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR compared to darunavir administered with 100 mg ritonavir in the evening.
h.Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of the components of VIEKIRA XR.
i. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.
NA: not available/not applicable; CI: Confidence interval
Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Doses of
ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg.
Dasabuvir was dosed twice daily and ombitasvir, paritaprevir and ritonavir were dosed once daily in all the above studies except studies with ketoconazole and carbamazepine that used single doses.

Microbiology

Mechanism of Action

VIEKIRA XR combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Dasabuvir

Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. In a biochemical assay, dasabuvir inhibited a panel of genotype 1a and 1b NS5B polymerases with median IC50 values of 2.8 nM (range 2.4 nM to 4.2 nM; n = 3) and 3.7 nM (range 2.2 nM to 10.7 nM; n = 4), respectively. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor.

Ombitasvir

Ombitasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of ombitasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Paritaprevir

Paritaprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, paritaprevir inhibited the proteolytic activity of recombinant HCV genotype 1a and 1b NS3/4A protease enzymes with IC50 values of 0.18 nM and 0.43 nM, respectively.

Antiviral Activity

Dasabuvir

The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. The median EC50 values of dasabuvir against HCV replicons containing NS5B genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.6 nM (range 0.4 nM to 2.1 nM; n = 11) and 0.3 nM (range 0.2 nM to 2 nM; n = 10), respectively.

Ombitasvir

The EC50 values of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 14.1 pM and 5 pM, respectively. The median EC50 values of ombitasvir against HCV replicons containing NS5A genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.68 pM (range 0.35 to 0.88 pM; n = 11) and 0.94 pM (range 0.74 to 1.5 pM; n = 11), respectively.

Paritaprevir

The EC50 values of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay were 1.0 nM and 0.21 nM, respectively. The median EC50 values of paritaprevir against HCV replicons containing NS3 genes from a panel of genotype 1a and 1b isolates from treatment-naïve subjects were 0.68 nM (range 0.43 nM to 1.87 nM; n = 11) and 0.06 nM (range 0.03 nM to 0.09 nM; n = 9), respectively.

Ritonavir

In HCV replicon cell culture assays, ritonavir did not exhibit a direct antiviral effect and the presence of ritonavir did not affect the antiviral activity of paritaprevir.

Combination Antiviral Activity

Evaluation of pairwise combinations of ombitasvir, paritaprevir, dasabuvir and ribavirin in HCV genotype 1 replicon cell culture assays showed no evidence of antagonism in antiviral activity.

Resistance

In Cell Culture

Exposure of HCV genotype 1a and 1b replicons to ombitasvir, paritaprevir or dasabuvir resulted in the emergence of drug resistant replicons carrying amino acid substitutions in NS5A, NS3, or NS5B, respectively. Amino acid substitutions in NS5A, NS3, or NS5B selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterized in genotype 1a or 1b replicons.

For dasabuvir, in HCV genotype 1a replicons single NS5B substitutions C316Y, M414I/T, E446K/Q, Y448C/H, A553T, G554S, S556G/R, and Y561H reduced dasabuvir antiviral activity by 8- to 1,472-fold. In genotype 1b replicons, single NS5B substitutions C316H/N/Y, S368T, N411S, M414I/T, Y448C/H, A553V, S556G and D559G reduced dasabuvir antiviral activity by 5- to 1,569-fold.

For ombitasvir, in HCV genotype 1a replicons single NS5A substitutions M28T/V, Q30E/R, L31V, H58D, and Y93C/H/L/N reduced ombitasvir antiviral activity by 58- to 67,000-fold. In genotype 1b replicons, single NS5A substitutions L28T, L31F/V, and Y93H reduced ombitasvir antiviral activity by 8- to 661-fold. In general, combinations of ombitasvir resistance-associated substitutions in HCV genotype 1a or 1b replicons further reduced ombitasvir antiviral activity.

For paritaprevir, in HCV genotype 1a replicons single NS3 substitutions F43L, R155G/K/S, A156T, and D168A/E/F/H/N/V/Y reduced paritaprevir antiviral activity by 7- to 219-fold. An NS3 Q80K substitution in a genotype 1a replicon reduced paritaprevir antiviral activity by 3-fold. Combinations of V36M, Y56H, or E357K with R155K or D168 substitutions reduced the activity of paritaprevir by an additional 2- to 7-fold relative to the single R155K or D168 substitutions in genotype 1a replicons. In genotype 1b replicons single NS3 substitutions A156T and D168A/H/V reduced paritaprevir antiviral activity by 7- to 159-fold. The combination of Y56H with D168 substitutions reduced the activity of paritaprevir by an additional 16- to 26-fold relative to the single D168 substitutions in genotype 1b replicons.

In Clinical Studies

In a pooled analysis of subjects treated with regimens containing dasabuvir, ombitasvir, paritaprevir, and ritonavir with or without ribavirin (for 12 or 24 weeks) in Phase 2b and Phase 3 clinical trials, resistance analyses were conducted for 64 subjects who experienced virologic failure (20 with on-treatment virologic failure, 44 with post-treatment relapse). Treatment-emergent substitutions observed in the viral populations of these subjects are shown in Table 4. Treatment-emergent substitutions were detected in all 3 HCV drug targets in 30/57 (53%) HCV genotype 1a infected subjects, and 1/6 (17%) HCV genotype 1b infected subjects.

Table 4. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of the Components of VIEKIRA XR with and without Ribavirin Regimens (12- or 24-week durations) in Phase 2b and Phase 3 Clinical Trials
Target Emergent Amino Acid Substitutions Genotype 1a N = 58a % (n) Genotype 1b N = 6 % (n)
NS3 Any of the following NS3 substitutions: V36A/M/T, F43L, V55I, Y56H, Q80L, I132V, R155K, A156G, D168(any), P334S, S342P, E357K, V406A/I, T449I, P470S, V23A (NS4A) 88 (51) 67 (4)
V36A/M/Tb 7 (4) --
V55Ib 7 (4) --
Y56Hb 10 (6) 50 (3)
I132Vb 7 (4) --
R155K 16 (9) --
D168 (any)d 72 (42) 67 (4)
D168V 59 (34) (3)
P334Sb,c 7 (4) --
E357Kb,c 5 (3) 17 (1)
V406A/Ib,c 5 (3) --
T449Ib,c 5 (3) --
P470Sb,c 5 (3) --
NS4A V23Ab -- 17 (1)
F43Lb, Q80Lb, A156G, S342Pb,c <5% --
NS5A Any of the following NS5A substitutions: K24R, M28A/T/V, Q30E/K/R, H/Q54Y, H58D/P/R, Y93C/H/N 78 (45) 33 (2)
K24R 5 (3) --
M28A/T/V 33 (19) --
Q30E/K/R 47 (27) --
H/Q54Y -- 17 (1)
H58D/P/R 7 (4) --
Y93C/N 5 (3) --
Y93H -- 33 (2)
NS5B Any of the following NS5B substitutions: G307R, C316Y, M414I/T, E446K/Q, A450V, A553I/T/V, G554S, S556G/R, G558R, D559G/I/N/V, Y561H 67 (38) 33 (2)
C316Y 4 (2) 17 (1)
M414I -- 17 (1)
M414T 5 (3) 17 (1)
A553I/T/V 7 (4) --
S556G/R 39 (22) 17 (1)
D559G/I/N/V 7 (4) --
Y561H 5 (3) --
G307R, E446K/Q, A450V, G554S, G558R <5% --

a. N = 57 for the NS5B target.
b.Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.
c. Position located in NS3 helicase domain.
d.D168A/F/H/I/L/N/T/V/Y.

Persistence of Resistance-Associated Substitutions

The persistence of dasabuvir, ombitasvir, and paritaprevir treatment-emergent amino acid substitutions in NS5B, NS5A, and NS3, respectively, was assessed in HCV genotype 1a-infected subjects in Phase 2 trials whose virus had at least 1 treatment-emergent resistance-associated substitution in the drug target, and with available data through at least 24 weeks post-treatment. Population and clonal nucleotide sequence analyses (assay sensitivity approximately 5-10%) were conducted to detect the persistence of viral populations with treatment-emergent substitutions.

For dasabuvir, viral populations with 1 or more treatment-emergent substitutions in NS5B persisted at detectable levels through at least Post-Treatment Week 24 in 11/16 (69%) subjects, and through Post-Treatment Week 48 in 8/15 (53%) subjects with available data. Treatment-emergent S556G persisted through Post-Treatment Week 48 in 6/9 (67%) subjects.

For ombitasvir, viral populations with 1 or more resistance-associated treatment-emergent substitutions in NS5A persisted at detectable levels through at least Post-Treatment Week 24 in 24/24 (100%) subjects, and through Post-Treatment Week 48 in 18/18 (100%) subjects with available data.

For paritaprevir, viral populations with 1 or more treatment-emergent substitutions in NS3 persisted at detectable levels through at least Post-Treatment Week 24 in 17/29 (59%) subjects, and through Post-Treatment Week 48 in 5/22 (23%) subjects with available data. Resistance-associated variant R155K remained detectable in 5/8 (63%) subjects through Post-Treatment Week 24, and in 1/5 (20%) subjects through Post-Treatment Week 48. Resistance-associated D168 substitutions remained detectable in 6/22 (27%) subjects through Post-Treatment Week 24, and were no longer detectable through Post-Treatment Week 48.

Among HCV genotype 1b infected subjects who experienced virologic failure with a regimen including ombitasvir and paritaprevir, a treatment-emergent NS5A Y93H substitution persisted through at least Post-Treatment Week 48 in 2/2 subjects, and a NS3 D168V treatment-emergent substitution persisted through Post-Treatment Week 24 in 2/4 subjects, but was no longer detectable through Post-Treatment Week 48 (0/4 subjects).

The lack of detection of virus containing a resistance-associated substitution does not indicate that the resistant virus is no longer present at clinically significant levels. The long-term clinical impact of the emergence or persistence of virus containing VIEKIRA XR-resistance-associated substitutions is unknown.

Effect of Baseline HCV Polymorphisms on Treatment Response

A pooled analysis of subjects in the Phase 3 clinical trials of dasabuvir, ombitasvir, and paritaprevir with or without ribavirin was conducted to explore the association between baseline HCV NS5B, NS5A, or NS3 resistance-associated polymorphisms and treatment outcome. Baseline samples from HCV genotype 1a infected subjects who experienced virologic failure (n=47), as well as samples from a subset of demographically matched subjects who achieved SVR (n=94), were analyzed to compare the frequencies of resistance-associated polymorphisms in these two populations. The NS3 Q80K polymorphism was detected in approximately 38% of subjects in this analysis and was enriched approximately 2-fold in virologic failure subjects compared to SVR-achieving subjects. Ombitasvir resistance-associated polymorphisms in NS5A (pooling data from all resistance-associated amino acid positions) were detected in approximately 22% of subjects in this analysis and similarly were enriched approximately 2-fold in virologic failure subjects. Dasabuvir resistance-associated polymorphisms in NS5B were detected in approximately 5% of subjects in this analysis and were not enriched in virologic failure subjects.

In contrast to the Phase 3 subset analysis, no association of NS3 or NS5A polymorphisms and treatment outcome was seen in an analysis of noncirrhotic HCV genotype 1a-infected subjects (n=174 for NS3 and n=183 for NS5A) who received dasabuvir, ombitasvir, and paritaprevir with or without ribavirin (for 12 or 24 weeks) in a Phase 2b trial.

Baseline HCV polymorphisms are not expected to have a substantial impact on the likelihood of achieving SVR when VIEKIRA XR is used as recommended for HCV genotype 1a and 1b infected patients, based on the low virologic failure rates observed in clinical trials.

Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B-palm inhibitors by class. Dasabuvir retained full activity against HCV replicons containing a single NS5B L159F, S282T, or V321A substitution, which are associated with resistance or prior exposure to nucleot(s)ide analogue NS5B polymerase inhibitors. In clinical trials of the components of VIEKIRA XR, no subjects who experienced virologic failure had treatment-emergent substitutions potentially associated with resistance to nucleot(s)ide analogue NS5B polymerase inhibitors.

The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5B inhibitors, NS5A inhibitors, or NS3/4A protease inhibitors has not been studied. Similarly, the efficacy of VIEKIRA XR has not been studied in subjects who have failed prior treatment with another NS5B inhibitor, NS5A inhibitor, or NS3/4A protease inhibitor.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Dasabuvir

Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (2000 mg per kg per day). Similarly, dasabuvir was not carcinogenic in a 2-year rat study up to the highest dose tested (800 mg per kg per day), resulting in dasabuvir exposures approximately 19-fold higher than those in humans at 500 mg.

Dasabuvir was not genotoxic in a battery of in vitro or in vivoassays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rat micronucleus assays.

Ombitasvir

Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (150 mg per kg per day). Similarly, ombitasvir was not carcinogenic in a 2-year rat study up to the highest dose tested (30 mg per kg per day), resulting in ombitasvir exposures approximately 16-fold higher than those in humans at 25 mg.

Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitroor in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.

Paritaprevir, ritonavir

Paritaprevir, ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dose tested (300/30 mg per kg per day). Similarly, paritaprevir, ritonavir was not carcinogenic in a 2-year rat study up to the highest dose tested (300/30 mg per kg per day), resulting in paritaprevir exposures approximately 9-fold higher than those in humans at 150 mg.

Paritaprevir was positive in an in vitro chromosome aberration test using human lymphocytes. Paritaprevir was negative in a bacterial mutation assay, and in two in vivo genetic toxicology assays (rat bone marrow micronucleus and rat liver Comet tests).

If VIEKIRA XR is administered with ribavirin, refer to the prescribing information for ribavirin for information on carcinogenesis, and mutagenesis.

Impairment of Fertility

Dasabuvir

Dasabuvir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 800 mg per kg per day. Dasabuvir exposures at this dose were approximately 16-fold the exposure in humans at the recommended clinical dose.

Ombitasvir

Ombitasvir had no effects on embryo-fetal viability or on fertility when evaluated in mice up to the highest dose of 200 mg per kg per day. Ombitasvir exposures at this dose were approximately 25-fold the exposure in humans at the recommended clinical dose.

Paritaprevir, ritonavir

Paritaprevir, ritonavir had no effects on embryo-fetal viability or on fertility when evaluated in rats up to the highest dose of 300/30 mg per kg per day. Paritaprevir exposures at this dose were approximately 2- to 5-fold the exposure in humans at the recommended clinical dose.

If VIEKIRA XR is administered with ribavirin, refer to the prescribing information for ribavirin for information on Impairment of Fertility.

Clinical Studies

Description of Clinical Trials

Table 5 presents the clinical trial design including different treatment arms that were conducted with the components of VIEKIRA XR with or without ribavirin in subjects with chronic hepatitis C (HCV) genotype 1 (GT1) infection. For detailed description of trial design and recommended regimen and duration [see Dosage and Administration and Clinical Studies].

Table 5. Clinical Trials Conducted with the Components of VIEKIRA XR With or Without Ribavirin (RBV) in Subjects with Chronic HCV GT1 Infection
Trial Population Study Arms and Duration (Number of Subjects Treated)
SAPPHIRE-I (double-blind) GT1 (a and b) TNa without cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (473)
  • Placebo for 12 weeks (158)
SAPPHIRE-II (double-blind) GT1 (a and b) TEb without cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (297)
  • Placebo for 12 weeks (97)
PEARL-II (open-label) GT1b TE without cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (88)
  • Components of VIEKIRA XR for 12 weeks (91)
PEARL-III (double-blind) GT1b TN without cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (210)
  • Components of VIEKIRA XR for 12 weeks (209)
PEARL-IV (double-blind) GT1a TN without cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (100)
  • Components of VIEKIRA XR for 12 weeks (205)
TURQUOISE-II (open-label) GT1 (a and b) TN & TE with compensated cirrhosis
  • Components of VIEKIRA XR + RBV for 12 weeks (208)
  • Components of VIEKIRA XR + RBV for 24 weeks (172)
TURQUOISE-III (open-label) GT1b TN & TE with compensated cirrhosis
  • Components of VIEKIRA XR for 12 weeks (60)

a. TN, treatment-naïve was defined as not having received any prior therapy for HCV infection.

b. TE, treatment-experienced subjects were defined as having failed to respond to prior treatment with pegIFN/RBV.

The components of VIEKIRA XR with RBV were also evaluated in the following two studies:

  • HCV GT1-infected liver transplant recipients (CORAL-I) [see Clinical Studies].
  • Subjects with HCV GT1 co-infected with HIV-1 (TURQUOISE-I) [see Clinical Studies].

In all clinical trials, the ombitasvir, paritaprevir, ritonavir dose was 25/150/100 mg once daily and the dasabuvir dose was 250 mg twice daily and doses were not adjusted. For subjects who received RBV, the RBV dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg. RBV dose adjustments were performed according to the RBV labeling.

In all clinical trials, sustained virologic response was defined as HCV RNA below the lower limit of quantification (

Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection without Cirrhosi

Subjects with Chronic HCV GT1a Infection without Cirrhosis

Subjects with HCV GT1a infection without cirrhosis treated with the components of VIEKIRA XR with RBV for 12 weeks in SAPPHIRE-I and -II and in PEARL-IV [see Clinical Studies] had a median age of 53 years (range: 18 to 70); 63% of the subjects were male; 90% were White; 7% were Black/African American; 8% were Hispanic or Latino; 19% had a body mass index of at least 30 kg per m2 ; 55% of patients were enrolled in US sites; 72% had IL28B (rs12979860) non-CC genotype; 85% had baseline HCV RNA levels of at least 800,000 IU per mL.

Table 6 presents treatment outcomes for HCV GT1a treatment-naïve and treatment-experienced subjects treated with the components of VIEKIRA XR with RBV for 12 weeks in SAPPHIRE-I, PEARL-IV and SAPPHIRE-II.

Treatment-naïve, HCV GT1a-infected subjects without cirrhosis treated with the components of VIEKIRA XR with RBV for 12 weeks in PEARL-IV had a significantly higher SVR12 rate than subjects treated with the components of VIEKIRA XR without RBV (97% and 90% respectively; difference +7% with 95% confidence interval, +1% to +12%). The components of VIEKIRA XR without RBV were not studied in treatment-experienced subjects with GT1a infection.

In SAPPHIRE-I and SAPPHIRE-II, no placebo subject achieved a HCV RNA <25 IU/mL during treatment.

Table 6. SVR12 for HCV Genotype 1a-Infected Subjects without Cirrhosis Who Were Treatment-Naïve or Previously Treated with PegIFN/RBV
  Components of VIEKIRA XR + RBV for 12 Weeks % (n/N)
GT1a treatment-naïve
SAPPHIRE-I SVR12 96% (308/322)
Outcome for subjects without SVR12  
On-treatment VF <1% (1/322)
Relapse 2% (6/314)
Other 2% (7/322)
PEARL-IV SVR12 97% (97/100)
Outcome for subjects without SVR12  
On-treatment VF 1% (1/100)
Relapse 1% (1/98)
Other 1% (1/100)
GT1a treatment-experienced
SAPPHIRE-II SVR12 96% (166/173)
Outcome for subjects without SVR12  
On-treatment VF 0% (0/173)
Relapse 3% (5/172)
Other 1% (2/173)
SVR12 by Prior pegIFN Experience  
Null Responder 95% (83/87)
Partial Responder 100% (36/36)
Relapser 94% (47/50)

Subjects with Chronic HCV GT1b Infection without Cirrhosis

Subjects with HCV GT1b infection without cirrhosis were treated with the components of VIEKIRA XR with or without RBV for 12 weeks in PEARL-II and -III [see Clinical Studies]. Subjects had a median age of 52 years (range: 22 to 70); 47% of the subjects were male; 93% were White; 5% were Black/African American; 2% were Hispanic or Latino; 21% had a body mass index of at least 30 kg per m2 ; 21% of patients were enrolled in US sites; 83% had IL28B (rs12979860) non-CC genotype; 77% had baseline HCV RNA levels of at least 800,000 IU per mL.

The SVR rate for HCV GT1b-infected subjects without cirrhosis treated with the components of VIEKIRA XR without RBV for 12 weeks in PEARL-II (treatment-experienced: null responder, n=32; partial responder, n=26; relapser, n=33) and PEARL-III (treatment-naïve, n=209) was 100%.

Clinical Trial Results in Adults with Chronic HCV Genotype 1a and 1b Infection and Compensated Cirrhosis

The components of VIEKIRA XR with and without ribavirin were evaluated in two clinical trials in patients with compensated cirrhosis.

TURQUOISE-II was an open-label trial that enrolled 380 HCV GT1 subjects with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Subjects were randomized to receive the components of VIEKIRA XR with RBV for either 12 or 24 weeks of treatment.

Treated subjects had a median age of 58 years (range: 21 to 71); 70% of the subjects were male; 95% were White; 3% were Black/African American; 12% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2 ; 43% of patients were enrolled in US sites; 82% had IL28B (rs12979860) non‑CC genotype; 86% had baseline HCV RNA levels of at least 800,000 IU per mL; 69% had HCV GT1a infection, 31% had HCV GT1b infection; 42% were treatment-naïve, 36% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 14% were prior pegIFN/RBV relapsers; 15% had platelet counts of less than 90 x 109 per L; 50% had albumin less than 4.0 mg per dL.

TURQUOISE-III was an open-label trial that enrolled 60 HCV GT1b-infected subjects with cirrhosis and mild hepatic impairment (Child-Pugh A) who were either treatment-naïve or did not achieve SVR with prior treatment with pegIFN/RBV. Subjects received the components of VIEKIRA XR without RBV for 12 weeks. Treated subjects had a median age of 61 years (range: 26 to 78); including 45% treatment-naïve and 55% pegIFN/RBV treatment-experienced; 25% were ≥65 years; 62% were male; 12% were Black; 5% were Hispanic or Latino; 28% had a body mass index of at least 30 kg per m2 ; 40% of patients were enrolled in US sites; 22% had platelet counts of less than 90 x 109 per L; 17% had albumin less than 35 g/L; 92% had baseline HCV RNA levels of at least 800,000 IU per mL; 83% had IL28B (rs12979860) non‑CC genotype.

Table 6 presents treatment outcomes for GT1a- and GT1b-infected treatment-naïve and treatment-experienced subjects.

In GT1a infected subjects, the overall SVR12 rate difference between 24 and 12 weeks of treatment with the components of VIEKIRA XR with RBV was +6% with 95% confidence interval (-0.1% to +13% with differences varying by pretreatment history).

Table 6. TURQUOISE-II: SVR12 for Chronic HCV Genotype 1-Infected Subjects with Cirrhosis Who Were Treatment-Naïve or Previously Treated with pegIFN/RBV
  GT1a (TURQUOISE-II) GT1b (TURQUOISE-III)
Components of VIEKIRA XR + RBV for 24 Weeks % (n/N) Components of VIEKIRA XR + RBV for 12 Weeks % (n/N) Components of VIEKIRA XR without RBV for 12 Weeks % (n/N)
SVR12 95% (115/121) 89% (124/140) 100% (60/60)
Outcome for subjects without SVR12
On-treatment VF 2% (3/121) <1% (1/140) 0
Relapse 1% (1/116) 8% (11/135) 0
SVR12 for Naïve 95% (53/56) 92% (59/64) 100% (27/27)
SVR12 by Prior pegIFN Experience     100% (33/33)
Null Responder 93% (39/42) 80% (40/50) 100% (7/7)
Partial Responder 100% (10/10) 100% (11/11) 100% (5/5)
Relapser 100% (13/13) 93% (14/15) 100% (3/3)

Effect of Ribavirin Dose Reductions on SVR12

Seven percent of subjects (101/1551) treated with the components of VIEKIRA XR with RBV had a RBV dose adjustment due to a decrease in hemoglobin level; of these, 98% (98/100) achieved an SVR12.

Clinical Trial of Selected Liver Transplant Recipients (CORAL-I)

The components of VIEKIRA XR with RBV were administered for 24 weeks to 34 HCV GT1-infected liver transplant recipients who were at least 12 months post transplantation at enrollment with normal hepatic function and mild fibrosis (Metavir fibrosis score F2 or lower). The initial dose of RBV was left to the discretion of the investigator with 600 to 800 mg per day being the most frequently selected dose range at initiation of the components of VIEKIRA XR and at the end of treatment.

Of the 34 subjects (29 with HCV GT1a infection and 5 with HCV GT1b infection) enrolled, (97%) achieved SVR12 (97% in subjects with GT1a infection and 100% of subjects with GT1b infection). One subject with HCV GT1a infection relapsed post-treatment.

Clinical Trial in Subjects with HCV/HIV-1 Co-infection (TURQUOISE-I)

In an open-label clinical trial 63 subjects with HCV GT1 infection co-infected with HIV-1 were treated for 12 or 24 weeks with the components of VIEKIRA XR with RBV. Subjects were on a stable HIV-1 antiretroviral therapy (ART) regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir boosted atazanavir or raltegravir. Subjects on atazanavir stopped the ritonavir component of their HIV-1 ART regimen upon initiating treatment with the components of VIEKIRA XR with RBV. Atazanavir was taken with the morning dose. The ritonavir component of the HIV-1 ART regimen was restarted after completion of treatment.

Treated subjects had a median age of 51 years (range: 31 to 69); 24% of subjects were black; 81% of subjects had IL28B (rs12979860) non-CC genotype; 19% of subjects had compensated cirrhosis; 67% of subjects were HCV treatment-naïve; 33% of subjects had failed prior treatment with pegIFN/RBV; 89% of subjects had HCV genotype 1a infection.

The SVR12 rates were 91% (51/56) for subjects with HCV GT1a infection and 100% (7/7) for those with HCV GT1b infection. Of the 5 subjects who were non-responders, 1 experienced virologic breakthrough, 1 discontinued treatment, 1 experienced relapse and 2 subjects had evidence of HCV re-infection post-treatment.

One subject had confirmed HIV-1 RNA >400 copies/mL during the post-treatment period. This subject had no evidence of resistance to the ART regimen. No subjects switched their ART regimen due to loss of plasma HIV-1 RNA suppression.

Durability of Response

In an open-label clinical trial, 92% of subjects (526/571) who received various combinations of the direct acting antivirals included in VIEKIRA XR with or without RBV achieved SVR12, and 99% of those who achieved SVR12 maintained their response through 48 weeks post-treatment (SVR48).