Ombitasvir/paritaprevir/ritonavir, when co-administered with dasabuvir, combines three direct-acting antiviral medicinal products with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Refer to the Summary of Product Characteristics of dasabuvir for its pharmacological properties.
Ritonavir is not active against HCV. Ritonavir is a CYP3A inhibitor that increases the systemic exposure of the CYP3A substrate paritaprevir.
Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication.
Paritaprevir is an inhibitor of 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.
The EC50 of ombitasvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays was 14.1 and 5 pM, respectively. The activity of ombitasvir was attenuated 11- to 13-fold in the presence of 40% human plasma. The mean EC50 of ombitasvir against replicons containing NS5A from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.66 pM (range 0.35 to 0.88 pM; n=11) and 1.0 pM (range 0.74 to 1.5 pM; n=11), respectively. Ombitasvir has EC50 values of 12, 4.3, 19, 1.7, 3.2, and 366 pM against replicon cell lines constructed with NS5A from single isolates representing genotypes 2a, 2b, 3a, 4a, 5a, and 6a, respectively.
The EC50 of paritaprevir against genotype 1a-H77 and 1b-Con1 strains in the HCV replicon cell culture assay was 1.0 and 0.21 nM, respectively. The activity of paritaprevir was attenuated 24 to 27 -fold in the presence of 40% human plasma. The mean EC50 of paritaprevir against replicons containing NS3 from a panel of treatment-naïve genotype 1a and 1b isolates in the HCV replicon cell culture assay was 0.86 nM (range 0.43 to 1.87 nM; n=11) and 0.06 nM (range 0.03 to 0.09 nM; n=9), respectively. Paritaprevir had an EC50 value of 5.3 nM against the 2a-JFH-1 replicon cell line, and EC50 values of 19, 0.09, and 0.68 nM against replicon cell lines containing NS3 from a single isolate each of genotype 3a, 4a, and 6a, respectively
Ritonavir did not exhibit a direct antiviral effect on the replication of HCV subgenomic replicons, and the presence of ritonavir did not affect the in vitro antiviral activity of paritaprevir.
Resistance to paritaprevir and ombitasvir conferred by variants in NS3 and NS5A respectively, selected in cell culture or identified in Phase 2b and 3 clinical trials were phenotypically characterised in the appropriate genotype 1a or 1b replicons.
In genotype 1a, substitutions F43L, R155K, A156T, and D168A/F/H/V/Y in HCV NS3 reduced susceptibility to paritaprevir. In the genotype 1a replicon, the activity of paritaprevir was reduced 20-, 37-, and 17-fold by the F43L, R155K and A156T substitutions, respectively. The activity of paritaprevir was reduced 96-fold by D168V, and 50- to 219-fold by each of the other D168 substitutions. The activity of paritaprevir in genotype 1a was not significantly affected (less than or equal to 3-fold) by single substitutions V36A/M, V55I, Y56H, Q80K or E357K. Double variants including combinations of V36LM, F43L, Y56H, Q80K or E357K with R155K or with a D168 substitution reduced the activity of paritaprevir by an additional 2 to 3-fold relative to the single R155K or D168 substitution. In the genotype 1b replicon, the activity of paritaprevir was reduced 76- and 159-and 337- fold by D168A, D168H, D168V, and D168Y respectively. Y56H alone could not be evaluated due to poor replication capacity, however, the combination of Y56H and D168A/V/Y reduced the activity of paritaprevir by 700- to 4118- fold.
In genotype 1a, substitutions M28T/V, Q30E/R, L31V, H58D, Y93C/H/N, and M28V + Q30R in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1a replicon, the activity of ombitasvir was reduced by 896-, 58- and 243-fold against the M28T/V and H58D substitutions, respectively, and 1326-, 800-, 155-foldand 1675- to 66740- fold by the Q30E/R, L31V and Y93C/H/N substitutions, respectively. Y93H, Y93N or M28V in combination with Q30R reduced the activity of ombitasvir by more than 42,802-fold. In genotype 1b, substitutions L28T, L31F/V, as well as Y93H alone or in combination with L28M, R30Q, L31F/M/V or P58S in HCV NS5A reduced susceptibility to ombitasvir. In the genotype 1b replicon, the activity of ombitasvir was reduced by less than 10-fold by variants at amino acid positions 30 and 31. The activity of ombitasvir was reduced by 661-, 77-, 284- and 142-fold against the genotype 1b substitutions L28T, Y93H, R30Q in combination with Y93H, and L31M in combination with Y93H, respectively. All other double substitutions of Y93H in combination with substitutions at positions 28, 31, or 58 reduced the activity of ombitasvir by more than 400-fold.
In genotype 4a, resistance to paritaprevir or ombitasvir by variants in NS3 or NS5A, respectively, selected in cell culture were phenotypically characterised. Substitutions R155C, A156T/V, and D168H/V in HCV NS3 reduced susceptibility to paritaprevir by 40- to 323-fold. Substitution L28V in HCV NS5A reduced the susceptibility to ombitasvir by 21-fold.
The pharmacokinetic properties of the combination of ombitasvir/paritaprevir/ritonavir with dasabuvir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. The table below shows mean Cmax and AUC of ombitasvir/paritaprevir/ritonavir 25 mg/150 mg/100 mg once daily with dasabuvir 250 mg twice daily following multiple doses with food in healthy volunteers.
Geometric mean Cmax, AUC of multiple doses of ombitasvir/paritaprevir/ritonavir 150 mg/100 mg/25 mg once daily with dasabuvir 250 mg twice daily with food in healthy volunteers:
| Cmax (ng/ml) (% CV) | AUC (ng*hr/ml) (% CV) | |
|---|---|---|
| Ombitasvir | 127 (31) | 1420 (36) |
| Paritaprevir | 1470 (87) | 6990 (96) |
| Ritonavir | 1600 (40) | 9470 (41) |
Ombitasvir, paritaprevir and ritonavir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir exposures increased in a dose proportional manner, paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is minimal for ombitasvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokinetic steady state for the combination is achieved after approximately 12 days of dosing.
The absolute bioavailability of ombitasvir and paritaprevir was approximately 50% when administered with food as ombitasvir/paritaprevir/ritonavir.
In the presence of paritaprevir/ritonavir, dasabuvir exposures decreased by approximately 50% to 60% while ombitasvir exposures increased by 31-47%.
In the presence of ombitasvir, paritaprevir exposures were minimally affected (5% to 27% change) while dasabuvir exposures increase by approximately 30%.
In the presence of dasabuvir, paritaprevir exposures increased by 50% to 65% while there was no change in ombitasvir exposures.
Ombitasvir, paritaprevir and ritonavir should be administered with food. All clinical trials with ombitasvir, paritaprevir and ritonavir have been conducted following administration with food.
Food increased the exposure (AUC) of ombitasvir, paritaprevir and ritonavir by up to 82%, 211% and 49%, respectively relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal). To maximise absorption, ombitasvir/paritaprevir/ritonavir should be taken with food without regard to fat or calorie content.
Ombitasvir, paritaprevir and ritonavir are highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in subjects with renal or hepatic impairment. The blood to plasma concentration ratios in humans ranged from 0.6 to 0.8 indicating that ombitasvir and paritaprevir were preferentially distributed in the plasma compartment of whole blood. Ombitasvir was approximately 99.9% bound to human plasma proteins. Paritaprevir was approximately 97-98.6% bound to human plasma proteins. Ritonavir was greater than 99% bound to human plasma proteins.
In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1 and OATP1B3.
Ombitasvir is metabolised via amide hydrolysis followed by oxidative metabolism. Following a 25 mg single dose of 14C-ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivity in human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity.
Paritaprevir is metabolised predominantly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200 mg/100 mg oral dose of 14C paritaprevir /ritonavir to humans, the parent drug was the major circulating component, accounting for approximately 90% of the plasma radioactivity. At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.
Ritonavir is predominantly metabolised by CYP3A and to a lesser extent, by CYP2D6. Nearly the entire plasma radioactivity after a single 600 mg dose of 14C-ritonavir oral solution in humans was attributed to unchanged ritonavir.
Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of ombitasvir was approximately 21 to 25 hours. Following a single 25 mg dose of 14C- ombitasvir approximately 90% of the radioactivity was recovered in faeces and 2% in urine. Unchanged parent drug accounted for 88% of total radioactivity recovered in faeces, indicating that biliary excretion is a major elimination pathway for ombitasvir.
Following dosing of ombitasvir/paritaprevir /ritonavir with or without dasabuvir, mean plasma half-life of paritaprevir was approximately 5.5 hours. Following a 200 mg 14C -paritaprevir dose with 100 mg ritonavir, approximately 88% of the radioactivity was recovered in faeces with limited radioactivity (8.8%) in urine. Metabolism as well as biliary excretion of parent drug contribute to the elimination of paritaprevir.
Following dosing of ombitasvir/paritaprevir /ritonavir, mean plasma half-life of ritonavir was approximately 4 hours. Following a 600 mg dose of 14C-ritonavir oral solution, 86.4% of the radioactivity was recovered in the faeces and 11.3% of the dose was excreted in the urine.
Ombitasvir and paritaprevir do not inhibit organic anion transporter (OAT1) in vivo and are not expected to inhibit organic cation transporters (OCT1 and OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. Ritonavir does not inhibit OAT1 and is not expected to inhibit OCT2, OAT3, MATE1 and MATE2K at clinically relevant concentrations.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would result in approximately 10% change in ombitasvir exposures, and ≤20% change in paritaprevir exposures. There is no pharmacokinetic information in patients >75 years.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, female subjects would have approximately 55% higher, 100% higher and 15% higher ombitasvir, paritaprevir and ritonavir exposures than male subjects. However, no dose-adjustment based on gender is warranted. A 10 kg change in body weight from 76 kg (median weight in the Phase 3 studies) would results in <10% change in ombitasvir exposures, and no change in paritaprevir exposures. Body weight is not a significant predictor of ritonavir exposures.
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, Asian subjects had 18% to 21% higher ombitasvir exposures, and 37% to 39% higher paritaprevir exposures than non-Asian subjects. The ritonavir exposures were comparable between Asians and non-Asians.
The changes in ombitasvir, paritaprevir, and ritonavir exposures in subjects with mild, moderate and severe renal impairment are not considered to be clinically significant. Limited data in patients with endstage renal disease indicate no clinically significant changes in exposure also in this patient group. No dose adjustment of ombitasvir/paritaprevir/ritonavir with and without dasabuvir is required for patients with mild, moderate or severe renal impairment , or end-stage-renal disease on dialysis.
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, with or without dasabuvir 400 mg were evaluated in subjects with mild (CrCl: 60 to 89 ml/min), moderate (CrCl: 30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment.
Compared to the subjects with normal renal function, ombitasvir exposures were comparable in subjects with mild, moderate and severe renal impairment. Compared to the subjects with normal renal function, paritaprevir Cmax values were comparable, but AUC values were 19%, 33% and 45% higher in mild, moderate and severe renal impairment, respectively. Ritonavir plasma concentrations increased when renal function was reduced: Cmax and AUC values were 26% to 42% higher, 48% to 80% higher and 66% to 114% higher in subjects with mild, moderate and severe renal impairment, respectively.
Following administration of ombitasvir/paritaprevir/ritonavir, the changes in ombitasvir, paritaprevir, and ritonavir exposures in subjects with mild, moderate and severe renal impairment were similar to those observed when ombitasvir/paritaprevir/ritonavir was administered with dasabuvir, and are not considered to be clinically significant.
Following administration of ombitasvir/paritaprevir/ritonavir and dasabuvir:
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg, with dasabuvir 400 mg were evaluated in non-HCV infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.
In subjects with mild hepatic impairment, paritaprevir, ritonavir and ombitasvir mean Cmax and AUC values decreased by 29% to 48%, 34% to 38% and up to 8%, respectively, compared to subjects with normal hepatic function.
In subjects with moderate hepatic impairment, ombitasvir and ritonavir mean Cmax and AUC values decreased by 29% to 30% and 30 to 33%, respectively, while paritaprevir mean Cmax and AUC values increased by 26% to 62% compared to subjects with normal hepatic function.
In subjects with severe hepatic impairment, paritaprevir mean Cmax and AUC values increased by 3.2-to 9.5-fold; ritonavir mean Cmax values were 35% lower and AUC values were 13% higher and ombitasvir mean Cmax and AUC values decreased by 68% and 54%, respectively, compared to subjects with normal hepatic function, therefore, ombitasvir/paritaprevir/ritonavir must not be used in patients with severe hepatic impairment.
In HCV-infected subjects, in comparison to those without cirrhosis, paritaprevir AUC increased to 2.2- to 2.4-fold for those with compensated cirrhosis (Child-Pugh A) and 3- to 4-fold for those with Child-Pugh B cirrhosis.
Following administration of ombitasvir/paritaprevir/ritonavir:
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg were not evaluated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment. Results from the pharmacokinetic evaluation of the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg, with dasabuvir 400 mg can be extrapolated to the combination of ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg.
The pharmacokinetics of ombitasvir/paritaprevir/ritonavir in paediatric patients has not been established.
Ombitasvir and its major inactive human metabolites (M29, M36) were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo mouse micronucleus assays.
Ombitasvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (150 mg/kg/day), resulting in ombitasvir AUC exposures approximately 26-fold higher than those in humans at the recommended clinical dose of 25 mg.
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 has shown malformations in rabbits at maximal feasible exposures 4-fold higher than the AUC exposure at recommended clinical dose. Malformations at low incidence were observed mainly in the eyes (microphthalmia) and teeth (absent incisors). In mice, an increased incidence of open eye lid was present in foetuses of dams administered ombitasvir; however, the relationship to treatment with ombitasvir is uncertain. The major, inactive human metabolites of ombitasvir were not teratogenic in mice at exposures approximately 26 times higher than in humans at the recommended clinical dose. Ombitasvir had no effect on fertility when evaluated in mice.
Unchanged ombitasvir was the predominant component observed in the milk of lactating rats, without effect on nursing pups. Ombitasvir-derived material was minimally transferred through the placenta in pregnant rats.
Paritaprevir was positive in an in vitro human chromosome aberration test. 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).
Paritaprevir/ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (300 mg/30 mg/kg/day), resulting in paritaprevir AUC exposures approximately 38-fold higher than those in humans at the recommended dose of 150 mg. Similarly, paritaprevir/ritonavir was not carcinogenic in a 2-year rat study up to the highest dosage tested (300 mg/30 mg/kg/day), resulting in paritaprevir AUC exposures approximately 8-fold higher than those in humans at 150 mg.
Paritaprevir/ritonavir has shown malformations (open eye lids) at a low incidence in mice at exposures 32/8-fold higher than the exposure in humans at the recommended clinical dose. Paritaprevir/ritonavir had no effects on embryo-foetal viability or on fertility when evaluated in rats at exposures 2- to 8-fold higher than the exposure in humans at the recommended clinical dose.
Paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk of lactating rats, without effect on nursing pups. Paritaprevir -derived material was minimally transferred through the placenta in pregnant rats.
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