Technivie
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Technivie - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Hepatitis C
Class: Antiviral combinations
Form: Tablets
Ingredients: ombitasvir, paritaprevir, ritonavir, colloidal silicon dioxide/anhydrous colloidal silica, copovidone, propylene glycol monolaurate, sodium stearyl fumarate, sorbitan monolaurate, vitamin E polyethylene glycol succinate

Pharmaceutical information

Ombitasvir Hydrate

Common name: ombitasvir
Chemical name: 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
Molecular formula and molecular mass: C50H67N7O8•4.5H2O (hydrate) 975.20 (hydrate)
Structural formula:



Physicochemical properties:
Appearance: Ombitasvir Hydrate is a white to light yellow to light pink powder.
Solubility: Ombitasvir Hydrate is practically insoluble in aqueous buffers but is soluble in ethanol.

Paritaprevir Hydrate

Common name: paritaprevir
Chemical name: (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
Molecular formula and molecular mass: C40H43N7O7S•2H2O (dihydrate) 801.91 (dihydrate)
Structural formula:



Physicochemical properties:
Appearance: Paritaprevir Hydrate is a white to off-white powder.
Solubility: Paritaprevir Hydrate has very low water solubility.

Ritonavir

Proper name: ritonavir
Chemical name: [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
Molecular formula and molecular mass: C37H48N6O5S2 720.95
Structural formula:



Physicochemical properties:
Appearance: Ritonavir is a white to off white to light tan powder.
Solubility: Ritonavir is insoluble in water and freely soluble in methanol and ethanol..

Clinical Trials

Trial Design

The efficacy and safety of ombitasvir, paritaprevir and ritonavir in patients with genotype 4 chronic hepatitis C infection was evaluated in a single clinical trial (PEARL-I), as summarized in Table 1. PEARL-I was a randomized, global multicenter, open-label trial that enrolled 135 adults with genotype 4 chronic hepatitis C infection without cirrhosis who were either treatment-naïve or did not achieve SVR with prior treatment with pegylated interferon/RBV (pegIFN/RBV). Treatment-naïve patients were randomized in a 1:1 ratio to receive ombitasvir tablets, paritaprevir tablets and ritonavir capsules with or without ribavirin for 12 weeks. PegIFN/RBV treatment-experienced patients received ombitasvir tablets, paritaprevir tablets and ritonavir capsules in combination with ribavirin for 12 weeks. The ombitasvir, paritaprevir, ritonavir dose was 25/150/100 mg once daily. The ribavirin dose was 1000 mg per day for patients weighing less than 75 kg or 1200 mg per day for patients weighing greater than or equal to 75 kg.

Table 1. Clinical Trial Name, Design, Treatment Regimen, Dosage and Duration of Treatment of GT 4 Infected Treatment-Naïve and Treatment-Experienced Patients without Cirrhosis
Study # Trial Design Regimen, Dosage and Number of Patients Duration of
treatment
Weeks
PEARL-I
(M13-
393)
Open-label, randomized to administer with or without RBV (paritaprevir tablet: 150 mg; ombitasvir tablet: 25 mg; ritonavir soft gelatin capsule: 100 mg) once daily (QD) + RBVa.

N=135
12 weeks

a; RBV, ribavirin tablets. The ribavirin dose was 1,000 mg per day for patients weighing less than 75 Kg and 1,200 mg per day for patients weighing ≥ 75 Kg.

Clinical Trial Results in Treatment-Naïve and Treatment-Experienced Adults with Genotype 4 Chronic Hepatitis C Infection

Demographic and baseline characteristics for adult patients with genotype 4 chronic hepatitis C infection in PEARL-I are provided in Table 2.

Table 2. Demographic and Baseline Characteristics of Treatment-Naïve and Treatment-Experienced HCV Genotype 4-Infected Patients without Cirrhosis in PEARL-I
Characteristics Ombitasvir + Paritaprevir +
Ritonavir ± RBV
12 Weeks
N = 135
n (%)
Age (years)
Median (range) 51 (19 - 70)
Gender
Male 88 (65.2)
Female 47 (34.8)
Race
White 120 (88.9)
Black or African American 12 (8.9)
Other 2 (1.5)
Multi-race 1 (0.7)
Ethnicity
Hispanic or Latino 8 (5.9)
None of the above 127 (94.1)
Body mass index
< 30 kg/m2 116 (85.9)
≥ 30 kg/m2 19 (14.1)
HCV genotype*
4a 50 (37.9)
4b 3 (2.3)
4d 68 (51.5)
4f 7 (5.3)
4 other** 3 (2.3)
4 (subtype could not be determined) 1 (0.8)
Treatment History
Treatment-naïve 86 (63.7)
Prior pegIFN/RBV null responder 23 (17.0)
Prior pegIFN/RBV partial responder 9 (6.7)
Prior pegIFN/RBV relapser 17 (12.6)
Baseline HCV RNA
Mean ± SD (log10 IU/mL) 6.17 + 0.53
< 800000 IU/mL, n (%) 41 (30.4)
≥ 800000 IU/mL, n (%) 94 (69.6)
IL28B
CC 29 (21.5)
Non-CC 106 (78.5)
Baseline fibrosis stage
F0-F1 104 (77.0)
F2 21 (15.6)
F3
F4 1 (0.7)
History of depression
No 120 (88.9)
Yes 15 (11.1)

* HCV genotype 4 subtype determined by phylogenetic analysis.

**One (1) each of 4c, 4g/k, and 4o.

Study Results

The SVR12 rates for HCV genotype 4-infected patients who were treatment-naïve or previously treated with pegIFN/RBV are summarized in Table 3. Sustained virologic response (virologic cure) was defined as HCV RNA below the lower limit of quantification (

Table 3. Sustained Virologic Response (SVR12) for HCV Genotype 4-Infected Patients who were Treatment-Naïve or Treatment-Experienced Patients Without Cirrhosis (PEARL-I)
Treatment outcome Ombitasvir + Paritaprevir
+ Ritonavirb
with RBV
12 weeks
Ombitasvir + Paritaprevir
+ Ritonavirb
No RBV
12 weeks
Treatment-naïve
% (n/N)
Treatment-experienceda
% (n/N)
Treatment-naïve
% (n/N)
Overall SVR12 100 (42/42) 100 (49/49) 91 (40/44)
95% CI 91.6 to 100 92.7 to 100 78.3 to 97.5
Outcome for Patients without
SVR12
On-treatment VFc 0 (0/42) 0 (0/49) 2 (1/44)
Relapsed 0 (0/42) 0 (0/49) 5 (2/42)
Othere 0 (0/42) 0 (0/49) 2 (1/44)

a; Patients previously treated with PegIFN alfa plus ribavirin.

b; Ombitasvir tablets, Paritaprevir Tablets and Ritonavir capsules were administered separately.

c; VF, Virologic Failure. On-treatment VF was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed increase from nadir in HCV RNA > 1 log10 IU/mL during treatment, or HCV RNA ≥ 25 IU/mL persistently during treatment with at least 6 weeks of treatment.

d; Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among patients with HCV RNA less than 25 IU/mL at last observation during at least 11 weeks of treatment.

e; Other includes subjects not achieving SVR12 but not experiencing on-treatment VF or relapse (e.g. lost to follow-up).

Paritaprevir total exposures (AUC) are 63% higher from the co-formulated tablet compared to the exposures from the tablet formulation used in PEARL-1.

Among 131 HCV GT4 infected patients in PEARL-I who achieved SVR12, virologic response data at post-treatment week 24 were available from 129 patients, and 129/129 (100%) patients maintained their response through 24 weeks post-treatment (SVR24).

Impact of Baseline Factors

Baseline viral load (< 800,000 IU/ml and ≥ 800,000 IU/ml) and host factors including gender, race, ethnicity, age, IL28B allele, baseline body mass index, history of depression, fibrosis stage, were not associated with SVR12 rate differences based on a limited number of patients.

Impact of Ribavirin Dose Adjustment on Probability of SVR

In the PEARL-I clinical trial, all patients (100%) receiving ombitasvir, paritaprevir, and ritonavir with ribavirin achieved SVR, including 7.7% of patients who had ribavirin dose adjustments during therapy.

Microbiology

Mechanism of Action

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

Paritaprevir

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. In a biochemical assay, paritaprevir inhibited the proteolytic activity of a recombinant HCV genotype 4a NS3/4A protease enzyme with a half maximal inhibitory concentration (IC50) value of 0.16 nM.

Paritaprevir inhibited the activity of NS3/4A enzymes from single isolates of genotypes 1a, 1b, 2a, 2b, and 3a with IC50 values of 0.18 nM, 0.43 nM, 2.4 nM, 6.3 nM, and 14.5 nM, respectively.

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.

Activity in Cell Culture and/or Biochemical Studies

Paritaprevir

The EC50 values of paritaprevir against HCV replicons containing NS3 from a single isolate of genotype 4a and 4d were 0.09 nM and 0.015 nM, respectively. Paritaprevir had EC50 values of 1.0 nM, 0.21 nM, 5.3 nM, 19 nM and 0.68 nM against replicon cell lines representing genotypes 1a-H77, 1b-Con1, 2a-JFH1, 3a and 6a, respectively.

Ombitasvir

The EC50 values of ombitasvir against HCV replicons containing NS5A from a single isolate of genotype 4a and 4d were 1.7 pM and 0.38 pM, respectively. Ombitasvir had EC50 values of 14 pM, 5.0 pM, 12 pM, 4.3 pM, 19 pM, 3.2 pM, and 366 pM against replicon cell lines representing genotypes 1a-H77, 1b-Con1, 2a, 2b, 3a, 5a and 6a, respectively.

Ritonavir

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 in Cell Culture

Exposure of HCV genotype 4a replicons to paritaprevir or ombitasvir resulted in the emergence of drug resistant replicons carrying amino acid substitutions in NS3 or NS5A, respectively. Amino acid substitutions in NS5A or NS3 selected in cell culture or identified in the clinical trial PEARL-I were phenotypically characterized in genotype 4 replicons. For paritaprevir, in the HCV genotype 4a replicon, NS3 substitutions R155C, A156T/V, and D168H/V reduced paritaprevir antiviral activity by 40- to 323-fold. In the HCV genotype 4d replicon, NS3 substitutions Y56H and D168V reduced paritaprevir antiviral activity by 8- and 313-fold, respectively, while a combination of Y56H and D168V reduced the activity of paritaprevir by 12,533-fold.

For ombitasvir, in the HCV genotype 4a replicon, NS5A substitution L28V reduced ombitasvir antiviral activity by 21-fold. In the HCV genotype 4d replicon, substitutions L28V alone and L28V in combination with T58S reduced ombitasvir antiviral activity by 310- and 760-fold, respectively. Ombitasvir retained full activity against the common NS5A polymorphisms M31I/L and T58A/P/S in NS5A in HCV genotype 4d.

Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response

Phylogenetic analysis of HCV sequences from genotype 4-infected patients in the clinical trial PEARL-I identified 7 HCV genotype 4 subtypes (4a, 4b, 4c, 4d, 4f, 4g/4k, 4o). Most patients were infected with either subtype 4a (37.9%) or 4d (51.5%). Baseline sequence analysis (n=132) indicated that amino acids at positions 28, 30, 31 and 58 in NS5A were polymorphic. Baseline polymorphisms were not observed at signature resistance-associated positions in NS3.

Baseline HCV polymorphisms are not expected to impact the likelihood of achieving SVR when TECHNIVIE is used as recommended to treat HCV genotype 4-infected patients, based on the low virologic failure rate observed in PEARL-I.

Resistance in Clinical Studies

In the clinical trial PEARL-I, three patients with HCV genotype 4 infection experienced virologic failure (2 post-treatment relapse, 1 on-treatment failure). All 3 virologic failures were observed with a regimen containing paritaprevir/ritonavir and ombitasvir without ribavirin and all 3 were infected with genotype 4d which was the predominant subtype isolated. None of these patients had resistance-conferring variants present at baseline. The predominant resistance-associated treatment-emergent variants at the time of failure were D168V (with or without Y56H) in NS3, and L28S and L28V (with or without T58S) in NS5A.

Persistence of Resistance-Associated Substitutions

The persistence of paritaprevir or ombitasvir resistance-associated amino acid substitutions in NS5A or NS3, respectively, in HCV genotype 4 has not been studied. The long-term clinical impact of the emergence or persistence of virus containing paritaprevir or ombitasvir resistance-associated substitutions is unknown.

Cross-resistance

Cross-resistance is expected among NS3/4A protease inhibitors and among NS5A inhibitors within each individual class. The impact of prior paritaprevir or ombitasvir treatment experience on the efficacy of other NS3/4A protease inhibitors or NS5A inhibitors has not been studied. Similarly, the efficacy of TECHNIVIE has not been studied in patients who have failed prior treatment with another NS3/4A protease inhibitor, NS5A inhibitor, or NS5B inhibitor.

Non-Clinical Toxicology

Repeat-Dose Toxicity

Paritaprevir/ritonavir

Paritaprevir/ritonavir was well tolerated in repeated-dose oral toxicity studies in mice, rats and dogs. No adverse findings were observed during paritaprevir/ritonavir repeat-dose toxicology studies up to and including 3-months duration in rats and CD-1 mice, and 9-months duration in dogs. The safety margins for studies in rat, mouse and dog were 22-, 87-, and 310-fold above the efficacious AUC of 4.8 mcg•hr/mL.

Paritaprevir/ritonavir associated adverse effects have been limited to the gallbladder of mice in a 6 month study in CD-1 mice. The adverse findings included focal erosion/ulceration, inflammation (both acute and chronic active), and epithelial hypertrophy/hyperplasia in some mice at paritaprevir exposures of 46-fold above the efficacious AUC. In contrast, gallbladder findings in the dog have been limited to minimal epithelial degeneration/necrosis. No evidence of disruption of the epithelial integrity has been noted in the dog, despite achieving exposures of up to 310-folds above the efficacious AUC. Importantly, the severity and character of the gallbladder change in the dog did not progress from the 1-month to the 9 month toxicology study, despite achieving higher exposures in the 9-month study as compared to the 1-month study.

Evaluation of paritaprevir/ritonavir in nonclinical species resulted in non-adverse changes in the rodent which were considered to be related to ritonavir. Findings in the rat and mouse included an increase in liver weight (microscopic correlate of hepatocellular hypertrophy) and an increase in serum triglycerides and cholesterol. Findings limited to the rat included hypertrophy of the thyroid follicular epithelium and an increase in transaminases (alanine aminotransferase and aspartate aminotransferase). These findings in both the rat and mouse were mild and reversible upon discontinuation of paritaprevir/ritonavir. The morphological changes in the liver and thyroid are consistent with adaptive findings reported in rodents administered compounds that result in hepatic microsomal enzyme induction. The thyroid follicular hypertrophy is considered to be secondary to disruption of thyroid hormone homeostasis secondary to hepatic enzyme induction and is not considered relevant for humans. Ritonavir-related effects were not present in the paritaprevir/ritonavir studies in dogs despite achieving higher exposures. The non-adverse effects in the rodent were present at ritonavir exposures approximately 2-fold above clinical exposure of 8.1 mcg•hr/mL. In contrast, these findings were not present in the dog at ritonavir exposures approximately 4-fold clinical exposure.

Ombitasvir

Ombitasvir was well tolerated without adverse effects in repeated-dose oral toxicity studies in mice, rats and dogs. Repeat dose toxicology studies were completed in mice (up to 6-months duration), rats (up to 3-months duration) and dogs (up to 6-months duration). Maximum achieved ombitasvir plasma exposures in the longest duration studies are at least 20-fold or higher as compared to human exposure at the clinical dose.

Both inactive, major, disproportionate human metabolites of ombitasvir (M29, M36) were negative in in vitro and in vivo genetic toxicology tests and did not cause adverse effects in 1-month repeat-dose and embryo-fetal developmental oral toxicity studies at AUC exposures that were ≥ 25-fold relative to anticipated human exposures.

Mutagenicity and Carcinogenicity

Paritaprevir/ritonavir

Paritaprevir was positive in an in vitro human 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).

Ritonavir has been tested for genotoxcicity in various in vitro and in vivo assays including bacterial mutation assay, mouse lymphoma assay, mouse micronucleus test and chromosomal aberration assay. Ritonavir was not mutagenic in any of the tests performed.

Paritaprevir/ritonavir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (300/30 mg per kg per day), resulting in paritaprevir AUC exposures approximately 56-fold higher and ritonavir exposure of 6-fold higher than those in humans at the clinical dose. Similarly, paritaprevir/ritonavir was not carcinogenic in a 2-year rat study up to the highest dosage tested (300/30 mg per kg per day), resulting in paritaprevir AUC exposures approximately 11-fold higher and ritonavir exposure of 6-fold higher than those in humans at the clinical dose.

TECHNIVIE is administered with ribavirin. Refer to the prescribing information for ribavirin for information on carcinogenesis and mutagenesis.

Ombitasvir

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 per kg per day), resulting in ombitasvir AUC exposures approximately 26-fold higher than those in humans at the recommended clinical dose of 25 mg.

The carcinogenicity study of ombitasvir in rats is ongoing.

Use with Ribavirin

Ribavirin was shown to be genotoxic in several in vitro and in vivo assays. Ribavirin was not carcinogenic in a 6-month p53+/- transgenic mouse study or a 2-year carcinogenicity study in rats. See the Product Monograph for ribavirin for additional information.

Reproduction and Teratology

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 AUC exposures at this dosage were approximately 6-fold and ritonavir 3-fold higher than 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 AUC exposures at this dosage were approximately 26-fold the exposure in humans at the recommended clinical dose.

Summary of Clinical Trials

Use with Ribavirin

In fertility studies in male animals, ribavirin induced reversible testicular toxicity. Refer to Product Monograph for ribavirin for additional information.