you a various types [75:99 >99.5 Blood-to-plasma ratio 0.49 0.7 0.6 0.7 Volume of distribution at steady state (Vss) (L) 173 103 21.5 c 149 Metabolism Metabolism amide hydrolysis followed by oxidative metabolism CYP3A4 (major), CYP3A5 CYP3A (major), CYP2D6 CYP2C8 (major), CYP3A Elimination d Major route of elimination biliary excretion metabolism metabolism metabolism t 1/2 (hr) e 21-25 5.5 4 5.5-6 % of dose excreted in feces f 90.2 88 86.4 94.4 % of dose excreted unchanged in feces f 87.8 1.1 33.8 26.2 % of dose excreted in urine f 1.91 8.8 11.3 ~ 2 % of dose excreted unchanged in urine f 0.03 0.05 3.5 0.03 NA - data not available Values refer to mean non-fasting/fasting ratios (90% CI) in systemic exposure (AUC). Moderate fat meal ~600 Kcal, 20-30% calories from fat. High fat meal ~900 Kcal, 60% calories from fat. Steady state exposures are achieved after approximately 12 days of dosing. It is apparent volume of distribution (V/F) for ritonavir. 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. t 1/2 values refer to the mean elimination half-life. 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. Table 7. Steady-State Pharmacokinetic Parameters of Ombitasvir, Paritaprevir, Ritonavir and Dasabuvir Following Oral Administration of Viekira Pak in HCV-Infected Subjects Pharmacokinetic Parameter a Ombitasvir Paritaprevir Ritonavir Dasabuvir C max (ng/mL) 68 262 682 667 AUC tau (ng*h/mL) b 1000 2220 6180 3240 Median values reported based on the population PK analysis. AUC 0-24 for ombitasvir, paritaprevir, ritonavir and AUC 0-12 for dasabuvir. Specific Populations Hepatic Impairment The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and dasabuvir 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, ombitasvir, paritaprevir and ritonavir AUC values decreased by 8%, 29% and 34%, respectively, and dasabuvir AUC values increased by 17% in subjects with mild hepatic impairment. Relative to subjects with normal hepatic function, ombitasvir, ritonavir and dasabuvir AUC values decreased by 30%, 30% and 16%, respectively, and paritaprevir AUC values increased by 62% in subjects with moderate hepatic impairment. Relative to subjects with normal hepatic function, paritaprevir, ritonavir and dasabuvir AUC values increased by 945%, 13%, and 325% respectively, and ombitasvir AUC values decreased by 54% in subjects with severe hepatic impairment [see Dosage and Administration ( 2.4 ), Contraindications (4 ), Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )] . Renal Impairment The single dose pharmacokinetics of ombitasvir, paritaprevir, ritonavir and dasabuvir were evaluated in non-HCV infected subjects with mild (CL cr : 60 to 89 mL/min), moderate (CL cr : 30 to 59 mL/min), and severe (CL cr : 15 to 29 mL/min) renal impairment. Overall, changes in exposure of ombitasvir, paritaprevir, ritonavir and dasabuvir in non-HCV infected subjects with mild-, moderate- and severe renal impairment are not expected to be clinically relevant. Pharmacokinetic data are not available on the use of Viekira Pak in non-HCV infected subjects with End Stage Renal Disease (ESRD). Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 19%, 42% and 21%, respectively, while ombitasvir AUC values were unchanged in subjects with mild renal impairment. Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 33%, 80% and 37%, respectively, while ombitasvir AUC values were unchanged in subjects with moderate renal impairment. Relative to subjects with normal renal function, paritaprevir, ritonavir and dasabuvir AUC values increased by 45%, 114% and 50%, respectively, while ombitasvir AUC values were unchanged in subjects with severe renal impairment [see Use in Specific Populations ( 8.7 )] . Pediatric Population The pharmacokinetics of Viekira Pak in pediatric patients less than 18 years of age has not been established [see Use in Specific Populations ( 8.4 )] . Sex No dose adjustment is recommended based on sex or body weight. Race/Ethnicity No dose adjustment is recommended based on race or ethnicity. Age No dose adjustment is recommended in geriatric patients [see Use in Specific Populations ( 8.5 )] . Drug Interaction Studies See also Contraindications ( 4 ), Warnings and Precautions ( 5.5 ), Drug Interactions ( 7 ) The effects of drugs discussed in Table 5 on the exposures of the individual components of Viekira Pak are shown in Table 8 . For information regarding clinical recommendations, see Drug Interactions ( 7 ) . Table 8. Drug Interactions: Change in Pharmacokinetic Parameters of the Individual Components of Viekira Pak 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 C max AUC C min Alprazolam 0.5 single dose 12 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) dasabuvir 0.93 (0.83, 1.04) 0.98 (0.87, 1.11) 1.00 (0.87, 1.15) Amlodipine 5 single dose 14 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) dasabuvir 1.05 (0.97, 1.14) 1.01 (0.96, 1.06) 0.95 (0.89, 1.01) Atazanavir/ ritonavir a Atazanavir 300 and ritonavir 100 once daily in the evening 11 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) dasabuvir 0.81 (0.73, 0.91) 0.81 (0.71, 0.92) 0.80 (0.65, 0.98) Carbamazepine 200 once daily followed by 200 twice daily 12 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 dasabuvir 0.45 (0.41, 0.50) 0.30 (0.28, 0.33) NA Carisoprodol 250 single dose 14 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) dasabuvir 0.96 (0.91, 1.01) 1.02 (0.97, 1.07) 1.00 (0.92, 1.10) Cyclobenzaprine 5 single dose 14 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) dasabuvir 0.98 (0.90, 1.07) 1.01 (0.96, 1.06) 1.13 (1.07, 1.18) Cyclosporine 30 single dose b 10 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) dasabuvir 0.66 (0.58, 0.75) 0.70 (0.65, 0.76) 0.76 (0.71, 0.82) Darunavir c 800 once daily 9 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) dasabuvir 1.10 (0.88, 1.37) 0.94 (0.78, 1.14) 0.90 (0.76, 1.06) Darunavir/ ritonavir d Darunavir 600 twice daily and ritonavir 100 once daily in the evening 7 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) dasabuvir 0.84 (0.67, 1.05) 0.73 (0.62, 0.86) 0.54 (0.49, 0.61) Darunavir/ ritonavir e Darunavir 800 and ritonavir 100 once daily in the evening 12 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) dasabuvir 0.75 (0.64, 0.88) 0.72 (0.64, 0.82) 0.65 (0.58, 0.72) Diazepam 2 single dose 13 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) dasabuvir 1.05 (0.98, 1.13) 1.01 (0.94, 1.08) 1.05 (0.98, 1.12) Ethinyl estradiol/ Norgestimate Ethinyl estradiol 0.035 and Norgestimate 0.25 once daily 7 f 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) dasabuvir 0.51 (0.22, 1.18) 0.48 (0.23, 1.02) 0.53 (0.30, 0.95) Everolimus 0.75 single dose 12 ombitasvir 0.99 (0.95, 1.03) 1.02 (0.99, 1.05) 1.02 (0.99, 1.06) paritaprevir 1.22 (1.03, 1.43) 1.26 (1.07, 1.49) 1.06 (0.97, 1.16) ritonavir 1.07 (0.99, 1.16) 1.05 (1.00, 1.10) 1.07 (1.02, 1.13) dasabuvir 1.03 (0.90, 1.18) 1.08 (0.98, 1.20) 1.14 (1.05, 1.23) Furosemide 20 single dose 12 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) dasabuvir 1.12 (0.96, 1.31) 1.09 (0.96, 1.23) 1.06 (0.98, 1.14) Gemfibrozil g 600 twice daily 11 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 dasabuvir 2.01 (1.71, 2.38) 11.25 (9.05, 13.99) NA Hydrocodone/ Acetaminophen 5/300 single dose 15 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) dasabuvir 1.13 (1.01, 1.26) 1.12 (1.05, 1.19) 1.16 (1.08, 1.25) Ketoconazole 400 once daily 12 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 dasabuvir 1.16 (1.03, 1.32) 1.42 (1.26, 1.59) NA Lopinavir/ ritonavir 400/100 twice daily 6 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) dasabuvir 0.99 (0.75, 1.31) 0.93 (0.75, 1.15) 0.68 (0.57, 0.80) Lopinavir/ ritonavir h 800/200 once daily 12 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) dasabuvir 0.56 (0.47, 0.66) 0.54 (0.46, 0.65) 0.47 (0.39, 0.58) Omeprazole 40 once daily 11 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) dasabuvir 1.13 (1.03, 1.25) 1.08 (0.98, 1.20) 1.05 (0.93, 1.19) Pravastatin 10 once daily 12 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) dasabuvir 1.00 (0.87, 1.14) 0.96 (0.85, 1.09) 1.03 (0.91, 1.15) Rilpivirine 25 once daily (morning) i 10 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) dasabuvir 1.18 (1.02, 1.37) 1.17 (0.99, 1.38) 1.10 (0.89, 1.37) Rosuvastatin 5 once daily 11 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) dasabuvir 1.07 (0.92, 1.24) 1.08 (0.92, 1.26) 1.15 (1.05, 1.25) Sirolimus 0.5 single dose j 11 ombitasvir 1.03 (0.93, 1.15) 1.02 (0.96, 1.09) 1.05 (0.98, 1.12) paritaprevir 1.18 (0.91, 1.54) 1.19 (0.97, 1.46) 1.16 (1.00, 1.34) ritonavir 1.00 (0.85, 1.17) 1.04 (0.94, 1.15) 1.10 (1.04, 1.17) dasabuvir 1.04 (0.89, 1.22) 1.07 (0.95, 1.22) 1.13 (1.01, 1.25) Tacrolimus 2 single dose 12 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) dasabuvir 0.85 (0.73, 0.98) 0.90 (0.80, 1.02) 1.01 (0.91, 1.11) Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of Viekira Pak. 30 mg cyclosporine was administered with Viekira Pak in the test arm and 100 mg cyclosporine was administered in the reference arm without Viekira Pak. Darunavir administered with Viekira Pak in the morning was compared to darunavir administered with 100 mg ritonavir in the morning. Darunavir administered with Viekira Pak 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. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after the morning dose of Viekira Pak compared to darunavir administered with 100 mg ritonavir in the evening. N=3 for dasabuvir. Study was conducted with paritaprevir, ritonavir and dasabuvir. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of Viekira Pak. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food. 0.5 mg sirolimus was administered with Viekira Pak in the test arm and 2 mg sirolimus was administered in the reference arm without Viekira Pak. NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Ombitasvir, paritaprevir and ritonavir were dosed once daily and dasabuvir was dosed twice daily in all the above studies except studies with gemfibrozil, ketoconazole and carbamazepine that used single doses. Table 9 summarizes the effects of Viekira Pak on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Drug Interactions ( 7 ) . Table 9. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Viekira Pak Co-administered Drug Dose of Co- administered Drug (mg) n Ratio (with/without Viekira Pak) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 C max AUC C min 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/ ritonavir a 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 dose d 10 1.01 (0.85, 1.20) c 5.82 (4.73, 7.14) c 15.80 (13.81, 18.09) c Darunavir e 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/ ritonavir f 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/ ritonavir g 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) Everolimus 0.75 single dose 12 4.74 (4.29, 5.25) 27.12 (24.5, 30.1) 16.10 (14.5, 17.9) Furosemide 20 single dose 12 1.42 (1.17, 1.72) 1.08 (1.00, 1.17) NA Ketoconazole 400 once daily 12 1.15 (1.09, 1.21) 2.17 (2.05, 2.29) NA Hydrocodone 5 single dose 15 1.27 (1.14, 1.40) 1.90 (1.72, 2.10) 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/ ritonavir h 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 Rosuvastatin 5 once daily 11 7.13 (5.11, 9.96) 2.59 (2.09, 3.21) 0.59 (0.51, 0.69) 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) Sirolimus 0.5 single dose j 11 6.40 (5.34, 7.68) c 37.99 (31.5, 45.8) c 19.55 (16.7, 22.9) c 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 Atazanavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of Viekira Pak. Atazanavir or darunavir or lopinavir parameters are reported. Dose normalized parameters reported. 30 mg cyclosporine was administered with Viekira Pak in the test arm and 100 mg cyclosporine was administeredin the reference arm without Viekira Pak. Darunavir administered with Viekira Pak in the morning was compared to darunavir administered with 100 mg ritonavir in the morning. Darunavir administered with Viekira Pak 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. Darunavir plus 100 mg ritonavir administered in the evening, 12 hours after morning dose of Viekira Pak compared to darunavir administered with 100 mg ritonavir in the evening. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of Viekira Pak. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food. 0.5 mg sirolimus was administered with Viekira Pak in the test arm and 2 mg sirolimus was administeredin the reference arm without Viekira Pak. NA: not available/not applicable; CI: Confidence interval Doses of ombitasvir, paritaprevir, and ritonavir were 25 mg, 150 mg and 100 mg. Doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures). Ombitasvir, paritaprevir and ritonavir were dosed once daily and dasabuvir was dosed twice daily in all the above studies except studies with ketoconazole and carbamazepine that used single doses. Microbiology Mechanism of Action Viekira Pak 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. 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 IC 50 values of 0.18 nM and 0.43 nM, respectively. 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 IC 50 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. Antiviral Activity Ombitasvir The EC 50 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 EC 50 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 EC 50 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 EC 50 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. Dasabuvir The EC 50 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 EC 50 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. 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 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. 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. In Clinical Studies In a pooled analysis of subjects treated with regimens containing ombitasvir, paritaprevir, and dasabuvir 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 10 . 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 10. Treatment-Emergent Amino Acid Substitutions in the Pooled Analysis of Viekira Pak 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 = 58 a % (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/T b 7 (4) -- V55I b 7 (4) -- Y56H b 10 (6) 50 (3) I132V b 7 (4) -- R155K 16 (9) -- D168 (any) d 72 (42) 67 (4) D168V 59 (34) 50 (3) P334S b,c 7 (4) -- E357K b,c 5 (3) 17 (1) V406A/I b,c 5 (3) -- T449I b,c 5 (3) -- P470S b,c 5 (3) -- NS4A V23A b -- 17 (1) F43L b , Q80L b , A156G, S342P b,c]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug Manufacturer AbbVie Inc. Drug Class Antiviral combinations Related Drugs antiviral combinations Harvoni , Truvada , Atripla , Genvoya , Triumeq , Stribild Hepatitis C Harvoni , Epclusa , ribavirin , Zepatier , Mavyret , Sovaldi , sofosbuvir , ledipasvir / sofosbuvir , Vosevi , daclatasvir , Daklinza , Pegasys , Intron A , Ribasphere , Olysio , sofosbuvir / velpatasvir , Rebetol , simeprevir , Moderiba , PegIntron , elbasvir / grazoprevir , glecaprevir / pibrentasvir , RibaPak , More... Viekira Pak Rating 10 User Reviews 6.9 /10 10 User Reviews 6.9 Rate it! Viekira Pak Images Viekira Pak ombitasvir 12.5 mg / paritaprevir 75 mg / ritonavir 50 mg (AV1 ) View larger images} } is significant
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