Approval date: XXXX, XX/XX/XXXX
Date of revision: XXXX XXXX XXXX
Apatinib Mesylate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Apatinib Mesylate Tablets
Trade name: Aetan
English name: Apatinib Mesylate Tablets
Hanyu Pinyin：Jiahuangsuan Apatini Pian
Ingredients
The main component of this product is Apatinib Mesylate
Chemical name: N-[4-(1-cyanocyclopentyl) phenyl]-2-(4-pyridinylmethyl)amino-3-pyridinecarboxamide methanesulfonate
Chemical structure formula.
Molecular formula: C24H23N5O-CH4SO3
Molecular weight: 493.58
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
It is indicated for patients with advanced gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction that has progressed or recurred after receiving at least two previous systemic chemotherapies. Patients should be in good general condition at the time of treatment.
【Specifications】.
As per Apatinib (C24H23N5O): (1) 0.425g; (2) 0.375g; (3) 0.25g.
Dosage】
This product should be used under the supervision of an experienced physician.
Recommended dose: 850 mg, once daily.
Dosage: Take orally, half an hour after meals (the time of daily dosing should be the same as possible), with warm boiled water. Doses of apatinib missed during the course of treatment cannot be supplemented.
Duration of treatment: Take continuously until disease progression or intolerable adverse reactions occur.
Dosing in patients with hepatic or renal insufficiency.
There are no relevant data on the effect of this product on patients with hepatic or renal insufficiency. It is recommended that patients with hepatic or renal insufficiency should use this product with caution under the guidance of a physician based on clinical conditions and laboratory test indices, and it is contraindicated in patients with severe hepatic or renal insufficiency.
Dose adjustment.
Adverse reactions should be monitored closely during the use of this product and adjusted as necessary to enable the patient to tolerate the treatment. Adverse reactions due to Apatinib can be managed by symptomatic treatment, discontinuation and dose adjustment. Dose adjustments in clinical studies occurred mostly in cycles 2 and 3 (28-day cycles).
In case of Grade 3/4 hematologic or non-hematologic adverse reactions, it is recommended to suspend the drug (no more than 2 weeks) until the symptoms resolve or disappear, and then continue to take the drug at the original dose; if the adverse reactions do not resolve after 2 weeks, it is recommended to adjust the dose under the guidance of a physician: (i) first dose adjustment: 750 mg once daily; (ii) second dose adjustment: 500 mg once daily (for dose adjustment Please refer to Table 1 below and the subsequent [Caution] for the method of dose adjustment). If a third dose adjustment is required, the drug will be permanently discontinued.
Table 1: Dose adjustment principles of Apatinib for advanced gastric cancer
Adverse reaction classification NCI classification of dose adjustment of the provisions of hematologic adverse reactions grade 3 suspension of the drug, until the adverse reactions return to ≤ grade 2, continue the drug at the original dose. If grade 3 or above adverse reactions occur again, continue to use the drug after adjusting one dose downward. grade 4 suspend the drug and continue to use the drug after adjusting one dose downward when the adverse reactions recover to ≤ grade 2. For non-hematologic adverse reactions of Grade 3, suspend the drug until the adverse reaction returns to ≤ Grade 1, and continue the drug at the original dose; if Grade 3 or above reoccurs, continue the drug after adjusting one dose downward. for Grade 4, suspend the drug until the adverse reaction returns to ≤ Grade 1, and continue the drug after adjusting one dose downward. Note: The above was evaluated using the National Cancer Institute designated Common Drug Toxic Reaction Grading Criteria (NCI-CTCAE4.0)
The product should be permanently discontinued in patients who develop gastrointestinal perforation, wound dehiscence requiring clinical management, fistula, severe bleeding, nephrotic syndrome, or hypertensive crisis. It should be temporarily discontinued in patients with moderate to severe proteinuria that still requires further confirmation or severe hypertension that has not been clinically controlled. The use of this product should be withheld until elective surgery (see [Precautions]).
[Adverse Reactions].
Clinical trial data provide some basis for determining the possible adverse events caused by the drug and their approximate incidence. Due to the highly variable conditions of clinical trials, the incidence of adverse events observed in trials for one drug cannot be directly compared with the incidence of adverse events observed in clinical trials for another drug and may not reflect the actual incidence in the clinic.
Information on adverse events associated with the use of apatinib mesylate in advanced gastric cancer was primarily obtained from a phase III, multicenter, randomized, placebo-controlled clinical trial (n=267). Subjects were patients with advanced gastric cancer who had failed second-line chemotherapy. Patients with ECOG (Eastern Collaborative Oncology Group) physical status score of 2 or higher, patients with a tendency to bleed from the gastrointestinal tract, patients with uncontrollable hypertension, patients with abnormal coagulation, patients with positive urine protein, patients with bilirubin ≥1.25 times the upper limit of normal, and patients with unhealed wounds from major surgery within 4 weeks were excluded from the trial. Patients. 176 patients were treated with 850 mg qd of this product. 72% of subjects received 2 or more cycles of treatment (28 days as a cycle). The incidence of adverse reactions (as judged by the National Cancer Institute’s Common Adverse Reaction Classification Criteria NCI-CTC AE 3.0) was 92.05% and 71.43% in the trial and placebo groups, respectively, and the incidence of grade 3/4 adverse reactions was 51.70% and 24.18%, respectively. Among the common adverse reactions (incidence ≥ 5%), those with statistically different incidence between the test and control groups included hematologic toxicity (leukopenia, granulocytopenia, thrombocytopenia) and non-hematologic toxicity (proteinuria, hypertension, hand-foot syndrome, malaise, hoarseness). The incidence of serious adverse reactions in the trial and control groups was 6.25% and 6.59%, respectively, and the common serious adverse reaction was upper gastrointestinal bleeding.
Another multicenter, randomized, double-blind, placebo-parallel-controlled phase II clinical study (n=141) in advanced gastric cancer that failed second-line therapy provided supporting data. A total of 47 subjects were treated with 850 mg qd in this study. Baseline characteristics of the study population were similar to those of phase III. 35 patients in the 850 mg qd group received 2 or more cycles of treatment (28 days for one cycle). the incidence of adverse reactions (as judged by NCI-CTC AE 3.0) in the 850 mg qd and placebo groups was 78.72% and 56.25%, respectively, and the incidence of grade 3/4 adverse reactions was 34.04% and 16.67%.
Table 2 lists the adverse reactions with an incidence of ≥5% and the grade 3/4 adverse reactions with an incidence of ≥2% in the safety database of the two studies combined.
Table 2. Adverse reactions with an incidence of ≥5% in the phase II and phase III clinical studies and
Grade 3/4 adverse reactions with an incidence of ≥2%
Symptoms 850 mg, qd group (N=223) Placebo group (N=139) All n (%) Grade 3/4
n(%)All
n(%)Grade 3/4
n(%) General condition Weakness 40(17.94)6(2.69)10(7.19)2(1.44) Mental and nervous system Headache/headache/dizziness 19(8.52)1(0.45)4(2.88)0 Gastrointestinal system Diarrhea 23(10.31)3(1.35)3(2.16)1(0.72) Loss of appetite 20(8.97)4( 1.79)4(2.88)1(0.72)fecal occult blood20(8.97)011(7.91)1(0.72)vomiting14(6.28)1(0.45)8(5.76)1(0.72)abdominal pain11(4.93)3(1.35)9(6.47)1(0.72)nausea11(4.93)1(0.45)8( 5.76)1(0.72)Gastrointestinal bleeding5(2.24)3(1.35)5(3.60)4(2.88)Respiratory, thoracic and mediastinal hoarseness15(6.73)02(1.44)0 Cardiovascular system Elevated blood pressure81(36.32)12(5.38)7(5.04)0 Skin and subcutaneous tissue system Hand-foot syndrome61( 27.35)17(7.62)3(2.16)1(0.72)Renal and urinary system Proteinuria90(40.36)6(2.69)19(13.67)0 Metabolic and nutritional status Hypoproteinemia16(7.17)2(0.90)5(3.60)0 Hypokalemia8(3.59)2(0.90)5(3.60)3( 2.16)Hypophosphatemia8(3.59)5(2.24)1(0.72)1(0.72)Hematologic system Leukopenia83(37.22)3(1.35)10(7.19)1(0.72)Granulocytopenia73(32.74)11(4.93)10(7.19)2(1.44)Thrombocytopenia52(23.32)7( 3.14)9(6.47)2(1.44)decreased hemoglobin35(15.70)9(4.04)23(16.55)5(3.60)decreased red blood cells12(5.38)1(0.45)2(1.44)0 laboratory tests elevated transaminases40(17.94)12(5.38)13(9.35)2(1.44)
Elevated total bilirubin 36(16.14)7(3.14)11(7.91)5(3.60)Elevated alkaline phosphatase 25(11.21)5(2.24)10(7.19)1(0.72)Elevated gamma-glutamyl transpeptidase 21(9.42)8(3.59)9(6.47)3(2.16)Elevated lactate dehydrogenase 12(5.38) 03(2.16)0
Adverse effects of special concern
Elevated blood pressure: In the phase III clinical study of apatinib for gastric cancer, a total of 62 patients (35.23%) in the trial group experienced elevated blood pressure, including 8 cases of grade 3 elevation and no grade 4 elevation; 5 cases in the placebo group experienced elevated blood pressure (5.49%), all of which were grade 1/2 and no grade 3/4 elevation occurred, and no hypertensive crisis occurred in either group. Most of the patients with elevated blood pressure occurred about 2 weeks after taking the drug, and most of the patients generally had good control of elevated blood pressure by combining antihypertensive drugs.
Proteinuria: In the phase III clinical study, a total of 78 patients (44.32%) in the trial group developed proteinuria, of which 4 were grade 3 and no grade 4 proteinuria occurred; 15 patients (16.48%) in the placebo group developed proteinuria, all of which were grade 1/2 and no grade 3/4 proteinuria occurred. Proteinuria generally occurred about 3 weeks after dosing and could be relieved by suspension of dosing or dose downward adjustment.
Hand-foot syndrome: In the phase III clinical study, hand-foot syndrome occurred in 49 patients (27.84%) in the trial group, 15 of whom had grade 3 and no grade 4 hand-foot syndrome. Grade 2 hand-foot syndrome occurred in one patient (1.10%) in the placebo group. Hand-foot syndrome mostly occurred about 3 weeks after taking the drug and could be reduced by symptomatic treatment.
Bleeding: In the phase III clinical study, the observed bleeding symptoms included gastrointestinal bleeding, vomiting, hemoptysis, fecal occult blood, urinary occult blood, skin bleeding spots, and hemorrhage from ruptured liver metastases. The incidence of bleeding in the test and control groups was 19.89% and 24.18%, respectively, and the incidence of moderate to severe bleeding was 3.41% and 7.69%, respectively. Patients who experienced fecal occult blood usually occurred within the 1st cycle after taking the drug.
Cardiac toxicity: In the phase III clinical study, 5 (2.84%) and 1 (1.10%) ECG abnormalities occurred in the trial and placebo groups, respectively, including sinus bradycardia, partial ST-T changes, heart rate slowing, QT interval prolongation, and acute myocardial infarction.
Hepatotoxicity: In the phase III clinical study, hepatotoxicity included elevated transaminases, bilirubin, alkaline phosphatase, γ-glutamyl transpeptidase, and lactate dehydrogenase after drug administration, with no significant difference in the occurrence between the test and placebo groups. Most of the liver enzyme abnormalities occurred at the beginning of the second cycle after taking the drug.
Contraindications
It is contraindicated in patients with active bleeding, ulcers, intestinal perforation, intestinal obstruction, within 30 days after major surgery, uncontrollable hypertension, grade III-IV cardiac insufficiency (NYHA criteria), and severe hepatic and renal insufficiency (grade 4).
[Precautions].
Special Precautions
Bleeding.
VEGFR inhibitor class antineoplastic drugs have the potential to increase the risk of bleeding. In phase II and III clinical studies of apatinib, patients with a propensity for gastrointestinal bleeding were excluded, and no significant increase in the risk of bleeding was found in this product relative to the placebo group. However, clinicians should still be cautioned to pay close attention when administering the drug. Patients with combined anticoagulation with warfarin should be routinely monitored for prothrombin time (APTT) and international normalized ratio (INR), and clinical signs of bleeding should be noted, and the drug should be discontinued promptly if signs of bleeding occur.
For patients with severe (grade 3/4) bleeding, suspension of the drug is recommended; if severe (grade 3/4) bleeding reoccurs after resumption of the drug, the drug may be continued after downward adjustment of one dose (see [DOSAGE AND ADMINISTRATION]), and discontinuation of the drug is recommended if adverse effects persist.
Patients with abnormal coagulation (APTT>1.5 x ULN or INR>1.5) were not included in the clinical studies with apatinib, therefore the risk of using apatinib in this population is not clear. This product should be used with caution in patients with abnormal coagulation. Prothrombin time and international normalized ratio should be closely monitored while taking this product, and suspension of the drug is recommended in case of severe (grade 3/4) abnormalities; if severe (grade 3/4) abnormalities occur again after resumption of the drug, the drug may be continued after downward adjustment of one dose (see [DOSAGE AND ADMINISTRATION]), and discontinuation of the drug is recommended if adverse reactions persist.
Cardiotoxicity: The administration of apatinib may cause electrocardiographic abnormalities, including prolonged QT interval or sinus bradycardia, as observed in clinical studies. It should be used with caution in patients with a known
patients with a known history of QT interval prolongation, patients taking antiarrhythmic drugs, or patients with associated underlying cardiac disease, bradycardia and electrolyte disturbances.
Close monitoring of electrocardiogram and cardiac function should be observed during drug administration. If Grade 3/4 adverse reactions occur, suspension of the drug is recommended. If Grade 3/4 adverse reactions occur again after resumption of the drug, the drug may be continued after downward adjustment of one dose (refer to the dose adjustment principles in Table 1), and if the adverse reactions persist, discontinuation of the drug is recommended. Discontinuation is recommended for patients with grade III-IV cardiac insufficiency or cardiac ultrasound examination showing left ventricular ejection fraction <50%.
Hepatotoxicity: Administration of apatinib has been observed in clinical studies to cause transient transaminase elevations or total bilirubin elevations. This product should be used with caution in patients with pre-existing elevations in serum transaminases and total bilirubin. It has not been studied in people with hepatic insufficiency and patients with prior hepatic insufficiency should be cautiously and closely monitored when taking apatinib (regular liver function testing, such as every 2 weeks, is recommended for the first 2 months of dosing). It is contraindicated in patients with severe hepatic insufficiency. If Grade 3/4 transaminases and total bilirubin are elevated, it is recommended that the drug be suspended and that serum transaminases and total bilirubin be monitored until their levels decrease significantly before resuming the drug; if Grade 3/4 adverse reactions occur again after resuming the drug, the drug may be continued at a lower dose (see [DOSAGE AND ADMINISTRATION]), or discontinued if the adverse reactions persist.
General Precautions
Elevated blood pressure: Elevated blood pressure is one of the most common adverse reactions to VEGFR inhibitor class antineoplastic drugs. In clinical studies, it has been observed that taking Apatinib can cause an increase in blood pressure, which is generally mild to moderate, mostly occurring about 2 weeks after taking the drug, and can generally be controlled with conventional antihypertensive drugs. Changes in blood pressure should be monitored routinely during administration, and if necessary, antihypertensive therapy or dose adjustment should be performed under the supervision of a specialist. If grade 3/4 blood pressure elevation occurs, suspension of the drug is recommended. If grade 3/4 blood pressure elevation occurs again after resumption of the drug, the drug may be continued after adjusting the dose downward by one dose (see [Dosage and Administration]), and discontinuation of the drug is recommended if adverse reactions persist. In patients with hypertensive crisis, the product should be discontinued during the occurrence.
Proteinuria: Proteinuria is one of the most common adverse reactions to VEGFR inhibitor class of antineoplastic drugs. Administration of Apatinib has been observed to cause proteinuria in clinical studies and should be used with caution and close monitoring when used in patients with renal insufficiency. Patients are advised to have regular urine tests, for example, every 2 weeks during the first 2 months of drug use and every 4 weeks thereafter, and to seek medical attention when proteinuria occurs. If proteinuria of grade ≥2 occurs, suspension of the drug is recommended; if proteinuria of grade ≥2 occurs again after resumption of the drug, the drug may be continued after downward adjustment of one dose (see [Dosage]), and discontinuation of the drug is recommended if adverse reactions persist.
Dermal toxicity: Hand-foot syndrome (painful erythema or erythema of the palms or soles of the feet) is the most common dermal adverse reaction following administration of this product and is usually mild to moderate (Grade 1-2). Grade 1 hand-foot syndrome is defined as the presence of any of the following: numbness, dullness/abnormal sensation, tingling, erythema and/or discomfort not interfering with normal activity in the hands and/or feet; Grade 2 is defined as painful erythema and/or swelling of the hands and/or feet and swelling and/or discomfort that interferes with the patient’s daily routine; Grade 3 is defined as wet flaking, ulceration, blistering or severe pain in the hands and/or feet and/or severe discomfort that prevents the patient from working or performing daily tasks. If hand-foot syndrome occurs, a number of necessary symptomatic supportive treatments may be taken under the direction of a physician, including: intensive skin care to keep the skin clean and avoid secondary infections; avoidance of pressure or friction; use of emollient creams or lubricants, topical lotions or lubricants containing urea and corticosteroid components; and topical antifungal or antibiotic therapy, if necessary. If three consecutive occurrences of ≥ grade 2 hand-foot syndrome with a tendency to worsen, suspension of the drug is recommended; if ≥ grade 2 hand-foot syndrome occurs again after resumption of the drug, the drug may be continued after downward adjustment of one dose (see [Dosage]), and if adverse reactions persist, discontinuation of the drug is recommended.
Diarrhea: The absorption of this product may be affected in patients with diarrhea, so the disease causing diarrhea should be actively treated and the product can be taken under the guidance of a physician after improvement.
If grade 3/4 diarrhea occurs while taking this product, it is recommended to suspend the drug; if grade 3/4 diarrhea occurs again after resuming the drug, the drug may be continued after adjusting one dose downward (see [Dosage]), and if the adverse reaction still persists, it is recommended to discontinue the drug.
Wound healing complications: No specific studies have been conducted on the effects of apatinib administration on wound healing. Patients with unhealed wounds from major surgery performed within 4 weeks were excluded from clinical studies of apatinib. Given the limited experience with when patients should take apatinib again after surgery, it is recommended that this product be temporarily discontinued prior to surgery and for 30 days after surgery.
Effects on the ability to drive and operate machinery: During treatment with this product, symptoms of weakness may occur and patients are advised to take care when driving or operating machinery.
Information for patients
1. No data are available on the combination of this product with other chemotherapeutic agents. If combined with other chemotherapeutic agents, the incidence and severity of adverse reactions may increase, so please use with caution under the guidance of a physician.
2. In animal studies, this product has been found to cause disorders of follicular development and spermatogenesis; therefore, men of childbearing age and women of childbearing age should take care of contraception during and for 8 weeks after discontinuation of the drug.
3. For patients with gastrointestinal perforation, wound dehiscence requiring clinical management, fistula, or nephrotic syndrome, this product should be discontinued during the period of occurrence.
[For pregnant and lactating women].
Pregnancy.
There is no information on the use of this product in women during pregnancy. Animal studies have shown that high doses of apatinib (16 mg/kg/day) administered to SD rats during organogenesis can delay skeletal development and have teratogenic effects in fetal rats. It is recommended that women of childbearing potential should use necessary contraception during and for at least 8 weeks after treatment with this product. If this product is administered during pregnancy, the patient should be informed of the possible hazards to the fetus, including developmental disorders and severe malformations.
Use during lactation.
No information is available on the use of this product in women who are breastfeeding. It is not known whether this product is excreted in human milk. Since many drugs are excreted in human milk, breastfeeding women are advised to discontinue breastfeeding during treatment with this drug.
Pediatric Use]
There is no information on the safety and efficacy of this product in patients under 18 years of age, and no references are available; therefore, this product is not recommended for patients under 18 years of age.
Geriatric use]
There is no clinical study data specifically for elderly patients. In the phase II and III clinical studies, elderly patients with advanced gastric cancer who were older than 60 years old and younger than 70 years old were enrolled in the phase II study.
qd group had 12 cases and 14 cases in the placebo group, and 73 cases in the trial group and 39 cases in the placebo group in the phase III study. No specific adverse reactions of clinical and laboratory tests were observed in these patients, and their efficacy was not significantly different from that of patients aged less than 60 years. For patients over 70 years of age, it is recommended to use with caution and adjust the dose of the drug under the guidance of physicians according to clinical conditions and laboratory test indices.
Drug Interactions]
No formal drug interaction studies have been conducted with this product.
Effects of CYP3A4 inhibitors and inducers on Apatinib
In vitro metabolism enzyme studies have shown that apatinib is mainly metabolized by CYP3A4, followed by CYP2D6, CYP2C9 and CYP2E1. Apatinib may increase the plasma concentration of apatinib when applied simultaneously with strong inhibitors of CYP3A4 (itraconazole, clarithromycin, voriconazole, telithromycin, saquinavir, ritonavir, etc.); it may decrease the plasma concentration of apatinib when applied simultaneously with inducers of CYP3A4 (dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, rifapentine, etc.). When it is necessary to combine with other drugs, it is recommended to choose alternative drugs that do not inhibit or induce CYP3A4 enzyme. If it is necessary to apply simultaneously with strong inhibitors or inducers of CYP3A4 enzyme, it is necessary to consider whether to make dose adjustment in combination with clinical observation.
Effect of Apatinib on other drugs
In vitro studies have shown that apatinib has a strong inhibitory effect on CYP3A4 and CYP2C9 (IC50<1 µM), so caution should be exercised during treatment with drugs that are primarily metabolized by CYP3A4, such as the calcium antagonists nisoldipine and lercanidipine, the HMG-CoA reductase inhibitors simvastatin and lovastatin, and midazolam, and caution should be exercised with drugs that are metabolized by The concomitant application of drugs metabolized by CYP2C9, such as warfarin, phenytoin, and certain sulfonylurea hypoglycemic agents such as glibenclamide.
Drugs that cause prolongation of the QT interval in the heart
As similar drugs have the toxic side effect of prolonging QT interval in clinical practice, the incidence of QT interval prolongation was observed to be 0.57% (1/176) in clinical studies of this product. Therefore, drugs that prolong QT interval should be used with caution during administration and ECG should be monitored closely during the administration period.
Other drugs with effects on liver and kidney function
Other drugs affecting liver and kidney function should be used with caution during the administration of this product, and liver and kidney function should be closely monitored during the administration of the drug.
Drug overdose
There is no known symptom of overdose of Apatinib, and there is no specific therapy for overdose of Apatinib. In the phase I clinical study, some patients received up to 1000 mg/day of apatinib, and the main adverse effects observed at this dose were grade 3/4 elevated blood pressure and grade 3 hand-foot syndrome.
If an overdose is suspected, the drug should be discontinued and the patient should be closely monitored and given appropriate supportive therapy.
Clinical studies]
The efficacy and safety of this product alone in advanced gastric cancer were evaluated in two randomized controlled studies.
A multicenter, randomized, double-blind, placebo-parallel-controlled phase III clinical study evaluated the efficacy and safety of apatinib in the treatment of advanced gastric cancer. The study enrolled 267 patients with advanced gastric cancer, including patients with adenocarcinoma of the gastroesophageal junction, who had previously failed second-line therapy (defined as treatment failure: intolerable toxicities, disease progression during treatment, or recurrence at the end of treatment). The median age of patients treated with apatinib was 58 years, and 75% were male; 27% had an ECOG score of 0 and 73% had an ECOG score of 1; about 60% had radical surgery, about 22% had total gastrectomy, and 35% had major gastrectomy; 68% had gastric cancer at the primary site and 22% had adenocarcinoma of the gastroesophageal junction; 21% had metastases with a cumulative organ count of more than 2 The first-line chemotherapy included fluorouracil, platinum, paclitaxel, and adriamycin, and the second-line chemotherapy was mainly based on irinotecan. Baseline characteristics and demographic data of subjects in the trial and placebo groups were balanced and comparable. Patients were randomized 2:1 to receive either apatinib tablets 850 mg once daily (n=176) or placebo once daily (n=91) in a 28-day cycle. The mean number of treatment cycles received by patients in the trial group was 2.9, with 72% of subjects receiving 2 or more cycles of treatment.
The primary efficacy evaluation metric for the study was overall survival (OS), and secondary efficacy metrics included progression-free survival (PFS), disease control rate (DCR), and objective remission rate (ORR). Median overall survival was prolonged in the trial group compared to the placebo group, reducing the risk of death by approximately 30%. The secondary endpoints of PFS and DCR were also higher than in the placebo group, and overall did not cause worsening of advanced gastric cancer-specific symptoms or health-related quality of life. The primary efficacy results are presented in Table 3, and the survival curves are shown in Figure 1.
Table 3. Key efficacy results of the phase III clinical study of apatinib for gastric cancer (FAS set)
Indicators Trial group (N=176) Placebo group (N=91) Overall survival (OS) Median (mOS, months) 6.54.7HR (95% CI) 0.709 (0.537, 0.937) Progression-free survival (PFS) Median (mPFS, months) 2.61.8HR (95% CI) 0.444 (0.331, 0.595) Objective remission rate (CR+PR) 2.84%0 clinical benefit rate (CR+PR+SD) 42.05%8.79% Note: FAS: full analysis set; mOS: median overall survival; mPFS: median progression-free survival; CR: complete remission; PR: partial remission; SD: stable disease.
Figure 1. Comparative analysis of the efficacy of survival (OS, months) in the two groups in the phase III study (FAS set)
Another multicenter, randomized, double-blind, placebo-parallel-controlled phase II clinical study was also conducted in patients with advanced gastric cancer who had failed second-line chemotherapy. 141 subjects were enrolled, including 48 in the placebo group, 47 in the 850 mg qd group, and 46 in the 425 mg bid group, with a 28-day cycle, and the primary endpoint was progression-free survival. RESULTS: The median progression-free survival was 3.7 months for patients in the 850 mg qd group and 3.2 months for patients in the 425 mg bid group, with statistically significant differences compared with the placebo group (P<0.0001). The median survival and objective remission rates of patients in both trial groups were higher than those in the placebo group. Key effectiveness data are presented in Table 4.
Table 4. primary effectiveness results of the phase II clinical study (FAS set)
Indicator 850 mg, qd group (N=47) Placebo group (N=48) Progression-free survival (PFS) Median (mPFS, months) 3.71.4HR (95% CI) 0.232 (0.133, 0.406) Overall survival (OS) Median (mOS, months) 4.82.5HR (95% CI) 0.513 (0.319, 0.826)Objective remission rate (CR+PR) 6.38%0Clinical benefit rate (CR+PR+SD) 51.06%10.42%Note: FAS: full analysis set; mOS: median overall survival; mPFS: median progression-free survival; CR: complete remission; PR: partial remission; SD: stable disease.
【Pharmacology and Toxicology】.
Pharmacological effects
Mechanism of action: It is a small molecule VEGFR-2 tyrosine kinase inhibitor, which can inhibit tumor angiogenesis. Animal studies have shown that this product can significantly inhibit tumor growth in various mouse tumor models.
Toxicological studies
Long-term toxicity: 26-week long-term toxicity studies in rats (5, 15, 50 mg/kg/day) showed no toxic response doses of 5 mg/kg (female rats) and 15 mg/kg (male rats). Toxic response doses were 15 mg/kg (female rats) and 50 mg/kg (male rats). Toxic reactions included elevated leukocytes and early onset of early chronic progressive nephropathy-like morphological changes in female rats; altered erythrocytes, broken incisors, decreased food consumption and mild changes in liver and kidney function in male and female rats, with the exception of incomplete recovery of incisors, which were largely recovered after discontinuation of the drug; long-term toxicity studies (20, 60, 120 mg/kg/day) in dogs for 39 weeks showed that only 20 mg/kg of spermatozoa in 1 male rat was used for the treatment. The long-term toxicity study (20, 60, 120 mg/kg/day) in dogs for 39 weeks showed that only 20 mg/kg impaired spermatogenesis in one male dog, but no other drug-related changes were observed, and no abnormal changes were seen during the recovery period.
Genotoxicity: Salmonella typhimurium reversion mutation test, Chinese hamster lung fibroblast chromosome aberration test and mouse bone marrow micronucleus test showed no genotoxicity of this product.
Reproductive toxicity: SD rats given 16 mg/kg/day by gavage on day 6-15 of gestation showed some degree of embryo-fetal toxicity, delayed fetal skeletal development and teratogenic effects, but no maternal toxicity. The non-toxic effect on embryo-fetus is 4 mg/kg.
Carcinogenicity studies have not been conducted.
Pharmacokinetics
The pharmacokinetics of this product was studied in 36 healthy subjects and 52 patients with metastatic solid tumors at different doses of single and multiple doses.
Absorption.
After single fasting oral doses of 250 mg, 500 mg and 750 mg in healthy subjects, absorption in vivo was rapid, with mean prodrug plasma concentrations peaking at approximately 1.7-2.3 h. Elimination was slow, with mean elimination half-lives of 7.9-9.4 h. In the 250 mg and 500 mg dose groups, prodrug plasma exposure was proportional to dose, and in the 750 mg dose group prodrug No further increase in exposure was seen. No significant gender differences were observed. The specific pharmacokinetic parameters are shown in Table 5.
Pharmacokinetic parameters of single fasting oral doses of 250 mg, 500 mg and 750 mg apatinib tablets in healthy subjects
Dose nCmax
(ng/ml)Tmax (h)AUC0-∞
(ng-h/ml)t1/2 (h)250 mg12656±3751.7±0.94222±22627.88±3.13500 mg121025±4222.3±1.08281±26289.03±3.92750 mg12785±3422.2±1.16414±29469.38± 3.80
After single postprandial fasting oral doses of 500 mg, 750 mg, and 850 mg in patients with metastatic solid tumors, absorption was slightly delayed, and the mean time to peak prodrug plasma concentration was approximately 3.9-5.1 h. The mean elimination half-life was 8.5-9.0 h. In the 500 mg and 750 mg dose groups, prodrug plasma exposure (AUC and Cmax) was proportional to dose, but the increase in prodrug exposure levels in the 850 mg dose group was proportionally lower than the increase in dose. The pharmacokinetic parameters are shown in Table 6.
Table 6. Pharmacokinetic analysis after a single fasting oral dose of 500 mg, 750 mg and 850 mg apatinib in patients with metastatic solid tumors
Dose nCmax (ng/ml)Tmax (h)AUC0-48
(ng-h/ml)t1/2 (h)500 mg
12840±6043.92±1.556226±41558.46±2.49750mg
91122±5912.78±0.639895±55369.07±1.29850mg
92528±24685.11±3.4422304±146888.99±2.06
The pharmacokinetic profile of 750 mg/day multiple dosing was examined in 11 patients with metastatic solid tumors. The results showed that no drug accumulation occurred in the subjects during continuous dosing (56 days).
The effect of eating on the absorption of apatinib was examined in patients with metastatic solid tumors (n=9, 6 men and 3 women), comparing the difference in absorption between a single oral dose of 750 mg/day 1 h before and 0.5 h after a meal. The results showed no significant effect of meal and dosing order on Tmax, Cmax, AUC and t1/2.
Statistically significant differences in the levels of exposure to apatinib and its metabolite M1 (Cmax and AUC) were observed in the 850 mg dose group of subjects of different genders in a study of single oral dosing in patients with metastatic solid tumors, with AUC 1.96-fold higher in women than in men and Cmax 3.57-fold higher. Due to the small sample size (5 cases in men and 4 cases in women), it is difficult to draw conclusions about this difference yet.
Age and weight had no significant effect on the pharmacokinetic profile of apatinib, so clinical use did not require dose adjustment based on these factors.
Correlation of dose levels with exposure levels.
In pharmacokinetic studies of single doses in patients with metastatic solid tumors, exposure levels of apatinib increased with increasing doses of oral administration, but not in a dose-proportional relationship.
Different tumor types
The pharmacokinetic profile was examined in a phase II study in patients with advanced colorectal cancer (n=40) and in patients with advanced gastric cancer (n=12), respectively. Patients with advanced colorectal cancer had similar pharmacokinetic parameters to healthy subjects at the same dose, while patients with gastric cancer had delayed absorption and lower exposure levels. Surgical treatment of the primary lesion (e.g., major gastrectomy) and the overall physical status of patients with advanced gastric cancer may affect drug dissolution and absorption.
Distribution.
The mean apparent volume of distribution in healthy subjects following single fasting oral doses of 250 mg, 500 mg, and 750 mg of apatinib mesylate tablets ranged from 929 to 2165 L. The plasma protein binding of apatinib plasma concentrations at 200 ng/ml was measured by ultrafiltration >86%.
Metabolism.
In vitro metabolic enzyme studies have shown that apatinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6, CYP2C9 and CYP2E1. In humans, apatinib is mainly metabolized by the liver, with the main metabolic pathways being E-3-hydroxylation, Z-3-hydroxylation, 25-N-oxidation, N-dealkylation, 16-hydroxylation, dihydroxylation, and O-glucuronide binding after E-3-hydroxylation.
After a single oral dose of 750 mg in healthy subjects, a total of 23 metabolites, including 17 phase I metabolites and 6 phase II metabolites, were detected in plasma in addition to the prodrug form, with E-3-hydroxyapatinib-O-glucuronide conjugate being the predominant metabolite in circulation at higher concentrations than the prodrug form, with no significant tyrosine kinase inhibitory activity by assay. The concentrations of the other major metabolites were lower than those of the prodrug.
Excretion.
Cumulative excretion of apatinib and its major metabolites via feces and urine was detected in healthy subjects 96 hours after a single oral dose of 750 mg of this product at approximately 77% of the dose administered, with excretion via feces at 69.8% of the dose, which was higher than that in urine (7.02%), thus judging that apatinib is primarily excreted in the feces after oral administration. Excretion in the fecal sample was mainly in the original form (59.0%). The urine sample was excreted mainly as metabolites, and the original form was almost undetectable.
Special populations
No pharmacokinetic studies have been conducted in special populations such as those with hepatic or renal insufficiency.
Storage
Store under 25℃ under shade and seal.
Packaging
10 tablets/plate, 1 plate/bag/box.
Expiration date
24 months.
Execution Standard
Approval number】
【Manufacturer】
Company Name: Jiangsu Hengrui Pharmaceutical Co.
Address: No. 38, Huanghe Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222047
Telephone number: 800-8283900 400-8283900
Fax number: 0518-85453845
Web address: http://www.hrs.com.cn