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Danorevir Sodium Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Danorevir Sodium Tablets
Trade name: GANOVO® (GANOVO®)
English name: Danoprevir Sodium Tablets
Hanyu Pinyin: Danuoruiweina Pian
Ingredients
The active ingredient of this product is Danoprevir Sodium.
Chemical name: ((2R,6S,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-2-((4-fluoroisodihydroindole-2-carbonyl)oxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropane[e] Pyrrolo[1,2-a][1,4]diazepentadecen-14a-carbonyl)cyclopropanesulfonamide sodium.
Chemical structure formula.
Molecular formula: C35H45FN5O9SNa
Molecular weight: 753.82
Properties
This product is film-coated tablets, white or off-white after removing the coating, containing light gray hidden spots.
Indications
This product should be combined with ritonavir, pegylated interferon alpha and ribavirin to form an antiviral regimen for the treatment of adult patients with non-cirrhotic genotype 1b chronic hepatitis C in primary care.
Specification
100mg (based on C35H46FN5O9S)
Dosage]
This product can be taken orally on an empty stomach or with food.
Dosage: 100mg twice a day for 12 weeks. Ritonavir, pegylated interferon alpha, and ribavirin must be administered concurrently with this product.
Recommended Ritonavir Tablets (RTV) Dosage: 100 mg orally twice daily for 12 weeks (see Ritonavir Tablets instructions for details).
Recommended pegylated interferon alpha (PEGIFNα) dosage: subcutaneous injection, 180 μg once a week for 12 weeks (see pegylated interferon alpha injection instructions for details).
Recommended Ribavirin dosage: Oral, 1000mg (body weight <75kg) or 1200mg (body weight ≥75kg) daily in 2 divided doses for 12 weeks (see instructions for Ribavirin formulation).
[Adverse Reactions].
The safety data of this product are mainly based on three phase II clinical trials and one phase III clinical trial, which included a total of 689 subjects, 645 of whom were taking the trial drug, including 383 patients with GT1b chronic viral hepatitis C. A total of 211 subjects from mainland China and 28 subjects from Taiwan, China were enrolled. In the three phase II trials, subjects were dosed at 50 mg to 200 mg for 12 to 24 weeks, and in the phase III trial, subjects were dosed at 100 mg for 12 weeks.
1. Chinese Phase III clinical study (CTR20160370)
In the Chinese phase III clinical study (CTR20160370), 141 patients with chronic hepatitis C received ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin, and the most common (incidence ≥10%) adverse reactions are shown in Table 1.
Table 1 Most common (≥10%) adverse reactions in clinical studies of treatment regimens consisting of ritonavir-enhanced danorevir sodium in combination with pegylated interferon α and ribavirin (CTR20160370)
System Organ Classification Incidence of Adverse Reactions (n/N) Hematologic and Lymphatic System Disorders Anemia 51.8% (73/141) Systemic Disorders and Administration Site Reactions Fever 34.8% (49/141) Malaise 30.5% (43/141) Flu-like illness 17.7% (25/141) Neurologic Disorders Headache 21.3% (30/141) Dizziness 14.2% (20/141) Metabolic and nutritional disorders decreased appetite 12.1% (17/141) Skin and subcutaneous tissue disorders rash 11.4% (16/141) Gastrointestinal disorders diarrhea 10.6% (15/141)
During the CTR20160370 study period, the majority of abnormal hematological examination values were grade 1 or 2. In total, 43 (30.5%) subjects showed abnormal values of grade 3/4 haematology tests (Table 2).
Table 2 Grade 3/4 abnormal hematology values in the clinical study of a regimen consisting of ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin (CTR20160370)
Hematologic abnormalities test group (N=141) Neutrophils grade 3 36 (25.5%) grade 4 2 (1.4%) Leukocytes grade 3 18 (12.8%) grade 4 0 Hemoglobin grade 3 6 (4.3%) grade 4 0 Platelets grade 3 2 (1.4%) grade 4 0 Lymphocytes grade 3 1 (0.7%) grade 4 0
The majority of abnormal blood biochemical tests during the CTR20160370 study were grade 1 or 2. In total, three (2.1%) subjects had abnormal grade 3/4 blood biochemical test values (Table 3).
Table 3 Grade 3/4 abnormal blood biochemistry values in the clinical study of a regimen consisting of ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin (CTR20160370)
Blood biochemical abnormalities test group (N=141) Triglycerides grade 3 1 (0.7%) grade 4 1 (0.7%) Glucose grade 3 1 (0.7%) grade 4 0 Uric acid grade 3 1 (0.7%) grade 4 0
The abnormal values of liver function-related laboratory tests that occurred in subjects during the CTR20160370 study were all grade 1 or 2, and no subjects had abnormal values of liver function-related laboratory tests with CTCAE ≥ grade 3. Elevated alanine aminotransferase (ALT) occurred in 20 (14.2%) subjects during the study period, of which 11 (7.8%) subjects experienced elevated ALT that was determined to be treatment regimen related; 16 (11.4%) subjects experienced elevated aspartate aminotransferase (AST), of which 9 (6.4%) subjects experienced elevated AST that was determined to be treatment The elevated total bilirubin (TBIL) occurred in 13 (9.2%) subjects, of which 10 (7.1%) subjects had elevated TBIL that was determined to be regimen related; 4 (2.8%) subjects had elevated DBIL, of which 2 (1.4%) subjects had elevated direct bilirubin (DBIL) that was determined to be regimen related (Table 4 ).
Table 4 Treatment regimen consisting of ritonavir-enhanced daunorubicin sodium in combination with pegylated interferon alpha and ribavirin
Clinical study (CTR20160370) Abnormal values of blood biochemical tests related to liver function (n (%))
Liver function-related indicators Grade 1 Grade 2 Grade 3 Grade 4 ALT 16 (11.4%) 4 (2.8%) – – AST 15 (10.6%) 1 (0.7%) – – TBIL 13 (9.2%) – – – DBIL 4 (2.8%) – – – 2. Chinese phase II clinical trial (Study CTR20150846)
All 70 subjects enrolled were treated with danorevir sodium/ritonavir in combination with pegylated interferon alpha and ribavirin, and 69 subjects completed 12 weeks of treatment. All subjects reported at least 1 adverse event; 1 serious adverse event was acute pancreatitis in 1 subject. 176 adverse reactions related to danorelvir sodium occurred in 40 subjects, and the most common (≥10% incidence) adverse reactions are shown in Table 5; the adverse reactions with an incidence of more than 30% were decreased neutrophil count, decreased white blood cell count, platelet count The most common adverse reactions (≥10%) are shown in Table 5.
Table 5 The most common (≥10%) adverse reactions during study CTR20150846 for the regimen consisting of ritonavir-enhanced danorevir sodium in combination with pegylated interferon α and ribavirin
Incidence of adverse reactions (n/N) Neutrophil count decreased 88.6% (62/70) White blood cell count decreased 82.9% (58/70) Platelet count decreased 52.9% (37/70) Anemia 52.9% (37/70) Influenza-like illness 42.9% (30/70) Headache 28.6% (20/70) Weakness 28.6% (20/70 ) Decreased lymphocyte count 28.6% (20/70) Fever 24.3% (17/70) Nausea 22.9% (16/70) Weight loss 17.1% (12/70) Dizziness 14.3% (10/70) Elevated bilirubin 14.3% (10/70) Hemolysis 14.3% (10/70) Decreased appetite 12.9% (9/70) Vomiting 12.9% (9/70) Diarrhea 11.4% (8/70) Rash 11.4% (8/70) Alopecia 11.4% (8/70) Hypertriglyceridemia 11.4% (8/70) Elevated aspartate aminotransferase 11.4% (8/70) Elevated alanine aminotransferase 10.0% (7/70) During combination therapy (Table 6), 19 ( 27.1%) subjects developed grade 3 neutropenia and 2 (2.8%) subjects developed grade 4 neutropenia; 8 (11.4%) subjects developed grade 3 leukopenia; 2 (2.9%) subjects developed grade 3 granulocytopenia; 1 (1.4%) subject developed grade 3 thrombocytopenia and 1 subject developed grade 4 thrombocytopenia One (1.4%) subject had grade 3 hemoglobinopenia (anemia). Blood biochemistry revealed one (1.4%) subject with one case of pegylated interferon alpha-related alanine aminotransferase elevation to 5 to 20 times the upper limit of normal (Table 7); this alanine aminotransferase elevation returned to within normal values during the study period.
Table 6 Abnormal CTCAE ≥ grade 3 hematology values during combination therapy
Abnormal hematology values Test group (N=70) Neutrophils grade 3 19 (27.1%) Grade 4 2 (2.9%) Leukocytes grade 3 8 (11.4%) Grade 4 – Granulocytes grade 3 2 (2.9%) Grade 4 – Platelets grade 3 1 (1.4%) Grade 4 1 (1.4%) Hemoglobin (anemia) grade 3 1 ( 1.4%)Grade 4- No clinically significant abnormal blood biochemical tests with >20 times the upper limit of normal values during the study treatment period in domestic clinical trials in combination therapy. Except for this, all other abnormal values of blood biochemical tests were within the range of 1 to 3 times the upper limit of normal values or 3 to 5 times the upper limit of normal values.
Table 7 Abnormal blood biochemical examination values of CTCAE≥3 during treatment
Abnormal blood biochemical values test group (N=70) ALT 5~20 times the upper limit of normal values1 (1.4%)>20 times the upper limit of normal values-during the combination therapy in the domestic clinical study, there were no abnormal blood biochemical test values within 5~20 times the upper limit of normal values associated with danorevir sodium; alanine aminotransferase or aspartate aminotransferase associated with danorevir sodium The elevation of alanine aminotransferase or aspartate aminotransferase associated with Danorevir sodium did not exceed 1 to 3 times the upper limit of normal values (Table 8).
Table 8 ALT and AST elevations associated with danorelvir sodium
1 to 3 times upper limit of normal 3 to 5 times upper limit of normal 5 to 20 times upper limit of normal> 20 times upper limit of normal ALT 5 (7.1%) – – – AST 6 (8.6%) – – – 3. Other global phase II clinical trials
Study NV22776.
A total of 417 cases were entered into the safety analysis, including 373 cases in the danorevir sodium/ritonavir/pegylated interferon alpha/ribavirin combination treatment trial group and 44 cases in the pegylated interferon alpha/ribavirin control group. Danorevir sodium dose 100 mg, 2/day. The treatment course was used for 9-24 weeks.
Common adverse events: Almost all subjects (97%-99%) experienced at least one adverse event during the study. Common adverse events reported (≥20% in the trial group) included malaise, fever, chills, weakness, nausea, diarrhea, pruritus, rash, hair loss, headache, myalgia, arthralgia, insomnia, cough, and decreased appetite. Adverse events that occurred at least 5% of the time and at least 10% more frequently in the trial group than in the control group were diarrhea, rash, hair loss, and decreased appetite. Most adverse events were mild to moderate.
Life-threatening adverse events: A total of five life-threatening adverse events were reported in the four subjects in the trial group. These included hypertension, coronary artery disease, acute myocardial infarction, and pneumonia which the investigator did not believe to be related to the trial drug. one case reported hyperuricemia which was thought to be possibly related to the study treatment.
Deaths: 2 deaths were reported during the study period. The causes of death were coronary heart disease and pneumonia, which the investigator evaluated as unrelated to the study drug.
Serious adverse events: 28 cases of serious adverse events were reported. The number of subjects who experienced at least 1 serious adverse event was 27 (7.2%) in the trial group and 1 (2%) in the control group, respectively. Four of these cases were acute pancreatitis (3 in the trial group) and one in the control group (1), which may be related to the treatment drug. Others were depression, acute renal failure, anemia and chest pain, which may be related to the therapeutic drugs.
Laboratory parameters: (1) liver function tests: a total of 10 cases reported elevated ACTG grade 3 ALT values; (2) lipid tests.
Elevated ACTG grade 3 cholesterol levels were reported in the trial group (1%-4%).
Study YV28218.
61 subjects entered the safety analysis, 34 in Group A on the drug for 11-12 weeks and 27 in Group B on the drug for >23 weeks.
Common Adverse Events: The majority of patients experienced at least one adverse event during treatment, including 97.1% of patients in Group A and 92.6% of patients in Group B. The most frequently reported adverse events (≥30% in each group) were anemia, neutropenia, and pruritus by preferred terminology. Adverse events reported in more than 10% of patients in each group during treatment included hematologic (anemia, leukopenia, thrombocytopenia), ocular disorders, digestive disorders (nausea, vomiting, digestive disturbances, mouth ulcers, abdominal pain), systemic conditions (fatigue, fever, malaise), infections (upper respiratory tract infections), metabolic and nutritional disorders (decreased appetite), skeletal-muscular disorders (myalgia), and neurological disorders (headache, vertigo), psychiatric disorders (insomnia), respiratory disorders (cough, dyspnea), skin and mucosal tissue disorders (pruritus, alopecia, rash). Most of the adverse events were mild or moderate.
Death: No deaths were reported during the study period.
Serious adverse events: Three serious adverse events were reported in three patients during the study period, one case of cellulitis, one case of upper respiratory tract infection, and one case of fracture. The investigators concluded that all serious adverse events were not related to the study treatment.
Laboratory tests: (1) Hematology: Grade 3 anemia was reported in 11 patients (14.7% in group A and 22.2% in group B). Grade 3 neutropenia was reported in 15 patients (23.5% in group A and 25.9% in group B).
Grade 4 neutropenia was reported in 4 patients (8.8% in group A and 3.7% in group B). Grade 3 lymphopenia was reported in 2 patients (7.4% in Group B); grade 4 lymphopenia was reported in 2 patients (2.9% in Group A and 3.7% in Group B). Grade 3 thrombocytopenia was reported in 3 patients (11.1% in group B). (2) Blood biochemistry: grade 3 amylase elevation was reported in 2 patients (2.9% in group A and 3.7% in group B).
Contraindication】
This product is contraindicated in patients with previous hypersensitivity to this product or any of the ingredients in this product.
For contraindications when this product is used in combination with other drugs, please refer to the instructions of the respective drugs.
Precautions】 1.
1. Ritonavir tablets, a pharmacokinetic enhancer, must be taken concurrently with this product. For more information about ritonavir tablets, please refer to the instruction manual of ritonavir tablets.
2. This product should be used in combination with interferon and ribavirin. Attention should be paid to possible anemia, neutropenia, leukopenia and thrombocytopenia. For more information on interferon and ribavirin, see the instructions for interferon and ribavirin.
For pregnant and lactating women]
There are no data on the use of this product in pregnant women.
It is not known whether any component of this product or its metabolites are secreted through human breast milk. Use with caution in nursing mothers.
Pediatric Use]
No data are available on the safety and efficacy of this product for use in pediatric patients.
Use in Elderly Patients
No safety and efficacy studies are available for use in elderly patients.
Drug Interactions
CYP3A inhibitors (e.g. ketoconazole) or inducers (e.g. rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine) may alter the blood levels of this product. When ritonavir tablets are combined with this product, the effect of other CYP3A inhibitors on increasing the blood concentration of this product is diminished. However, CYP3A inducers may reduce the blood concentration of both this product and ritonavir tablets.
Organic anion-transporting peptide inhibitors (e.g., cyclosporine, rifampin) and substrates (e.g., resulvastatin) may increase blood concentrations of this product. Concurrent use of organic anion-transporting peptide inhibitors and substrates should be avoided when taking this product.
This product is to be taken concomitantly with ritonavir tablets. Consideration should be given to avoiding drugs that interact with ritonavir tablets, as described in the ritonavir tablet insert for more information.
Nine Drug-Drug Interaction (DDI) clinical studies have been completed (Table 9). Ritonavir-enhanced danorevir sodium was studied for possible interactions with 11 other drugs.
Table 9 DDI studies of ritonavir-enhanced daunorubicin sodium (DNVr)
Study drug results Interaction drug Danorevir sodium ritonavir involving metabolic enzymes DDI of ketoconazole phase ketoconazole AUC ↑ 3.5-fold, Cmax- AUC ↑ 1.4-fold, Cmax- AUC- of raltegravir RAL, Cmax ↑ 30% AUC- Cmax↑27% AUC-, Cmax↑24% efavirenz AUC-, Cmax- AUC and Cmax both ↓0.7-fold AUC and Cmax both ↓0.7-fold DDI cyclosporine involving drug transport proteins Cyclosporine AUC↑3.7-fold,
Cmax ↑1.4-fold AUC ↑13.6-fold, and
Cmax ↑7.2-fold AUC ↑2-fold, Cmax ↑2-fold DDI involving food and acid suppressants low-fat or high-fat diet No significant effect on the PK of daunorubicin sodium on
Ritonavir
No significant effect on PK of ranitidine or omeprazole No significant effect on plasma exposure of danorevir sodium No significant effect on plasma exposure of ritonavir Other DDI Escitalopram Citalopram AUC ↓ 32%, Cmax ↓ 7% AUC-, Cmax-AUC-, Cmax-methadone Methadone AUC-, Cmax-AUC-, Cmax-AUC-, Cmax-AUC-, Cmax-AUC-, Cmax-AUC-, Cmax-AUC- Cmax- Dirinavir Dirinavir AUC-, Cmax-AUC ↑1.8, Cmax ↑1.6-fold AUC and Cmax both ↓0.7-fold Tenofovir had no effect on tenofovir plasma exposure No effect on danorevir sodium plasma exposure No effect on ritonavir plasma exposure Atazanavir had no effect on ATZ plasma exposure AUC ↑5-fold, Cmax ↑3-fold AUC and Cmax both ↑50%
[Drug overdose].
There is limited clinical experience with drug overdose of danorevir sodium tablets.
[Clinical trial].
One phase II and one phase III clinical study were completed in China to support the efficacy and safety of ritonavir-enhanced danorevir sodium tablets in combination with pegylated interferon alpha and ribavirin in patients with chronic viral hepatitis C genotype 1b.
Chinese Phase III Clinical Study (CTR20160370)
In the domestic clinical trial (CTR20160370) using ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin tablets for the treatment of genotype 1 chronic hepatitis C patients with primary non-cirrhotic liver disease, the trial used a multicenter, open single-arm trial design with a 4-week screening period, a 12-week treatment period and a 24-week end-of-treatment follow-up period. Subjects were patients with a confirmed diagnosis of chronic viral hepatitis C genotype 1, non-cirrhotic and not receiving any interferon and/or other direct antiviral medications. The treatment regimen was ritonavir 100 mg/danorevir sodium tablets 100 mg, 2/day; pegylated interferon alpha injection, 180 μg once weekly; ribavirin tablets, 500 mg or 600 mg twice daily; and a 12-week course. The primary endpoint was the rate of subjects achieving SVR12.
One hundred and forty-one subjects were enrolled, ranging in age from 19 to 72 years, with a mean of 42 years; 71 males accounted for approximately 50.4% and 70 females for approximately 49.7%. The mean weight of the subjects was 62.1 kg, the mean height was 1.64 m, and the mean body mass index was 23.0 kg/m2; the mean HCV RNA level in the subjects at baseline was approximately 6.04 log10 IU/mL (approximately 1.1 million IU/mL), and all subjects had non-cirrhotic livers at screening. All subjects were HCV GT1-infected, of which 3 (2.1%) were HCV GT1a-infected and 138 (97.9%) were HCV GT1b-infected.
The results of the study showed that the rate of subjects achieving SVR12 as the primary endpoint after 12 weeks of treatment with ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin was 96.5% (FAS) and 97.1% (PPS). The lower limit of the 95% CI interval for the rate of subjects achieving SVR12 was greater than 75% (a predetermined cut-off value for superiority), a statistically significant difference (see Table 10).
Table 10 Rate of Subjects Achieving SVR12
Subjects experienced a rapid decrease in HCV RNA levels and a sustained increase in virologic response rate in all of the first 4 weeks of the treatment period; the virologic response rate ranged from 96.5% to 99.3% during the period from 4 weeks of treatment to 12 weeks of follow-up after the end of treatment (Table 11).
Table 11 Virologic response rates over time in the CTR20160370 clinical study
Phase Time FAS %(n/N) PPS %(n/N) During treatment 1 week 49.7 (70/141) 49.3 (69/140) 2 weeks of treatment 85.8 (121/141) 86.4 (121/140) 4 weeks of treatment (RVR4) 98.6 (139/141) 99.3 (139/140) 8 weeks of treatment 99.3 ( 140/141) 100.0 (140/140) 12 weeks of treatment 98.6 (139/141)* 99.3 (139/140)* Post-treatment follow-up period 4 weeks after the end of treatment (SVR4) 97.2 (137/141) 97.9 (137/140) 12 weeks after the end of treatment (SVR12) 96.5 (136/141) 97.1 (136/140) Note: *1 subject did not receive an end-of-treatment visit and end-of-treatment virologic response data are missing.
There was no virological breakthrough during treatment, and only 4 (2.9%, 4/140) subjects experienced relapse at the end of treatment (Table 12).
Table 12 Results of subjects who did not achieve SVR12 in the CTR20160370 clinical study
Virological breakthrough during treatment 0% (0/140) Relapse 2.9% (4/140) Amino acid site substitution at relapse D168A, R155K
Chinese phase II clinical study (CTR20150846)
A multicenter, open, single-arm trial design was used in a domestic clinical trial using ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin tablets for the treatment of genotype 1 chronic hepatitis C patients with primary non-cirrhotic liver disease. All screened eligible subjects were treated with the combination regimen for 12 weeks and followed for 24 weeks after the end of treatment. Subjects were non-cirrhotic chronic hepatitis C patients with primary treatment genotype 1. The treatment regimen was ritonavir intensive 100 mg/danorevir sodium tablets 100 mg, 2/day; combined with pegylated interferon alpha injection, 180 μg each time, once a week; and ribavirin tablets, 500 mg or 600 mg each time, twice a day; for 12 weeks. The primary endpoint was the rate of subjects achieving SVR12.
The 70 subjects ranged in age from 22 to 66 years, with a mean of 41.2 years; 40 were approximately 57.1% male and 30 were approximately 42.9% female; the mean weight was 67.3 kg, the mean height was 1.67 m, and the mean body mass index was 24.0 kg/m2; the mean HCV RNA level in subjects at baseline was approximately 6.06 log10 IU/mL (1.16 million IU/mL), and all subjects were free of cirrhosis at baseline. All subjects were HCV GT1b-infected.
The results of the study showed that the rate of subjects achieving SVR12 after 12 weeks of ritonavir-enhanced danorevir sodium in combination with pegylated interferon alpha and ribavirin was 94.3% (FAS) and 95.7% (PPS) (Table 13).
Table 13 Rate of subjects who obtained SVR12 in the CTR20150846 clinical study
Total Subjects Genotype Regimen SVR12, % (n/N) FAS PPS 70 Genotype 1 12 weeks 94.3% (66/70) 95.7% (66/69) Note: 1) FAS (Full Analysis Set) is defined as all screened and eligible enrolled subjects who used the study drug at least once and had at least one post-administration evaluation data (1) FAS (Full Analysis Set) refers to the set of subjects who were screened and enrolled, used the study drug at least once, and had at least one post-drug evaluation data.
(2) PPS (Per-Protocol Set) refers to the set of subjects who met the inclusion criteria, did not meet the exclusion criteria, and completed the treatment protocol.
Subjects showed a rapid decrease in HCV RNA levels and a sustained increase in virological response rate during the first 4 weeks of the treatment period; the virological response rate of subjects ranged from 94.3% to 98.6% from the beginning of 4 weeks of treatment to 12 weeks after the end of treatment (Table 14).
Table 14 Virologic response rates over time in the CTR20150846 clinical study
Phase Time FAS % (n/N) PPS % (n/N) Treatment period Treatment 1 week 40.0 (28/70) 40.6 (28/69) Treatment 2 weeks 78.6 (55/70) 78.3 (54/69) Treatment 4 weeks (RVR4) 98.6 (69/70) 100 (69/69) Treatment 8 weeks 98.6 (69/70) 100 (69 /69)12 weeks of treatment 98.6 (69/70)100 (69/69)Post-treatment follow-up period 4 weeks after the end of treatment (SVR4)97.1 (68/70)98.6 (68/69)12 weeks after the end of treatment (SVR12)94.3 (66/70)95.7 (66/69)
There was no virological breakthrough during the treatment period and only 3 (4.3%, 3/69) subjects experienced relapse at the end of treatment (Table 15).
Table 15 Results of subjects who did not achieve SVR12 in the CTR20150846 clinical study
Virological breakthrough during the treatment period 0% (0/69) Relapse 4.3% (3/69) Amino acid site substitution at relapse D168E
[Pharmacology and Toxicology
Pharmacological effects
Danorevir sodium is an HCV NS3/4A serine protease inhibitor. NS3/4A protease activity is required for the HCV life cycle, and Danorevir sodium binds to NS3/4A protease to form a complex with a low dissociation rate, preventing viral polypeptide cleavage.
Toxicological studies
Genotoxicity: Danorevir sodium Ames test, mouse lymphoma test and rat micronucleus test results were negative.
Reproductive toxicity.
No significant effects on fertility were observed in male or female rats at doses of Danorevir sodium at 100, 300, and 800 mg/kg/day (male rats) and 30, 100, and 300 mg/kg/day (female rats). Maternal toxicity was seen at 100 and 300 mg/kg/day, including reduced body weight gain, reduced food intake, excessive salivation, fur disorder, and perioral red matter. 2 male rats died at 800 mg/kg/day.
No developmental toxicity was observed in embryo-fetus developmental toxicity tests in rats (30, 100, 300 mg/kg/day) and rabbits (30, 60, 120 mg/kg/day). Maternal toxicity was seen at a dose of 120 mg/kg/day of Danorevir sodium, including slowed body weight gain, reduced food intake, little and no stool, mild water loss, abortion in one, rales in two pregnant rabbits, and red material on the fur. No significant maternal toxicity was observed in rats at any dose.
In the perinatal toxicity test in rats, no maternal or F1 generation reproductive or developmental toxicity was observed at doses up to 300 mg/kg/day. Less than 1% of Danorevir sodium was secreted through breast milk.
Carcinogenicity.
In a 2-year carcinogenicity test in rats administered by gavage at doses of 25, 75 and 200 mg/kg/day in males and 50, 150 and 400 mg/kg/day in females, no carcinogenicity was observed.
Pharmacokinetics
The pharmacokinetic study was conducted in Chinese healthy subjects at a single dose of 100 mg. The results of the study showed that the oral dose of Danorevir sodium was rapidly absorbed in Chinese healthy subjects, with a peak time of approximately 1.5 hours. The apparent volume of distribution was about 8600 L, indicating a significant tissue accumulation characteristic of the product. The drug is rapidly metabolized and cleared in vivo, with a mean plasma clearance half-life of approximately 1.0 hour. Compared with a single oral dose of daunorivir sodium, ritonavir 100 mg significantly increased plasma exposure to daunorivir sodium, with a significantly higher median Cmax for plasma daunorivir sodium (29.7 ng/mL) than for daunorivir sodium orally alone (8.7 ng/mL); the median AUC0-24 for plasma daunorivir sodium (117.9 ng-h/mL) was approximately 7 times higher than the The median AUC0-24 (15.2 ng-h/mL) of danorevir sodium orally alone; the plasma elimination half-life was prolonged from 1 hour to approximately 3.2 hours, the total in vivo clearance was reduced to 1/6 of that of the single agent, and the apparent volume of distribution was reduced to 1/2 of that of the single agent, suggesting that ritonavir reduces the metabolic clearance of danorevir sodium and also reduces the tissue distribution of danorevir sodium, resulting in a The plasma exposure of danorevir sodium was significantly increased. The plasma drug concentration of danorevir sodium reached steady state after 6-7 days of continuous oral danorevir sodium/ritonavir (q12h), and the plasma drug concentration of danorevir sodium did not show significant accumulation at steady state. Plasma exposure was slightly higher in female subjects than in males, but the inter-individual variation in AUC was significantly higher in female subjects (over 80%) than in males (~18%), and the inter-individual variation in Cmax was similar, suggesting some gender differences in the metabolic elimination characteristics of this product.
A pharmacokinetic study in Chinese CHC patients showed that inter-individual variation in plasma trough concentrations of danorevir sodium at steady state was significant, with a distribution in the range of 0.2 ~ 11.1 ng/mL. After multiple doses, the plasma elimination half-life of ritonavir sodium was slightly shorter, no significant differences in Cmax and AUC were observed, and no plasma drug accumulation was observed. At steady state, ritonavir plasma drug concentrations were significantly higher than after the first dose, with an accumulation ratio of approximately 2.8 (based on AUC0-12) and less inter-individual variability in Cmin than for danorevir sodium. The plasma exposure of daunorivir sodium in Chinese CHC patients after continuous oral administration of daunorivir sodium/ritonavir 100mg/100mg (q12h) tablets was significantly higher than that in healthy subjects, and the plasma elimination half-life of daunorivir sodium was shortened.
Storage]
Airtight, store in a dry place.
Packaging
Oral solid medicine in high density polyolefin bottle, 28 tablets/bottle.
Expiration date
24 months.
Execution standard
xxxxxxxx
Approval number
State Drug Certification Hxxxxxxxx
Manufacturer
Company Name: Ge Li Pharmaceutical (Zhejiang) Co.
Production Address: No. 1, Yunhai Road, Lihai Town, Binhai New City, Shaoxing City, Zhejiang Province
Postal Code: 312366
Telephone number: 0571-56663383
Fax number: 0571-85389730
Medical consultation telephone number: 0571-56663383; Monday to Friday 9:00~17:00 (except holidays)
Website: www.ascletis.com.cn