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Axitinib (Inlyta) instructions
Common name: Axitinib
Trade name: Inlyta
All names: axitinib, Inlyta, axitinib, axitinib, Inlyta, Axit ix
1. Indications of axitinib
Axitinib is used for adult patients with advanced renal cell carcinoma (RCC) who have failed previous treatment with a tyrosine kinase inhibitor or cytokine.
2. Axitinib usage and dosage
Only doctors with experience in tumor treatment can use axitinib treatment.
Recommended Dosage
The recommended starting oral dose of axitinib is 5 mg twice daily. Axitinib can be taken with food or on an empty stomach, with two daily doses administered approximately 12 hours apart (see Pharmacokinetics). Axitinib should be taken with a glass of water.
Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs that cannot be controlled by concomitant use or dose adjustment.
If the patient vomits or misses a dose, another dose should not be taken. The next prescribed dose should be taken as usual.
3. Guidelines for dose adjustment of axitinib
It is recommended to increase or decrease the dose based on individual differences in patient safety and tolerability.
During treatment, the dose can be increased for patients who meet the following criteria: able to tolerate axitinib for at least two weeks of continuous treatment, no adverse reactions above grade 2 (according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE]), normal blood pressure, and not receiving antihypertensive drug treatment. When dose escalation is recommended starting at 5 mg BID, the axitinib dose can be increased to 7 mg BID and then further increased to 10 mg BID using the same criteria.
During treatment, the treatment of some adverse drug reactions may require suspending or permanently discontinuing axitinib administration, or reducing the dose of axitinib (see [Precautions]). If tapering from 5 mg BID is required, the recommended dose is 3 mg BID. If further reduction is necessary, the recommended dose is 2 mg BID.
Concomitant use of strong CYP3A4/5 inhibitors: Concomitant use of strong CYP3A4/5 inhibitors (such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) should be avoided. It is recommended to choose drugs with no inhibitory potential of CYP3A4/5 or weak inhibitory potential of CYP3A4/5 as alternative combination drugs. Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if coadministration with a strong CYP3A4/5 inhibitor is necessary, it is recommended to reduce the axitinib dose by half because it is expected that the dose reduction will adjust the area under the axitinib plasma concentration-time curve (AUC) to the AUC range without coadministration with the inhibitor. Subsequent dosage increases or decreases may be based on individual differences in patient safety and tolerability. If coadministration with a strong inhibitor is discontinued, the axitinib dose should be restored (after 3 to 5 inhibitor half-lives) to the dose used prior to initiating dosing with the strong CYP3A4/5 inhibitor (see Drug Interactions and Pharmacokinetics).
Coadministration of axitinib, a strong CYP3A4/5 inducer, with a strong CYP3A4/5 inducer may reduce the plasma concentration of axitinib (see Drug Interactions). It is recommended to select drugs with no or minimal potential to induce CYP3A4/5 as alternative concomitant drugs.
Although axitinib dose adjustment has not been studied in patients receiving strong CYP3A4/5 inducers, a gradual increase in the axitinib dose is recommended if coadministration with a strong CYP3A4/5 inducer is necessary. Maximal induction of high-dose potent CYP3A4/5 inducers has been reported to occur within one week of co-treatment with the inducer. If the dose of axitinib is increased, patients should be carefully monitored for toxicity. Treatment of some adverse drug reactions may require withholding or permanently discontinuing axitinib therapy and/or reducing the axitinib dose (see Precautions). If coadministration with a strong CYP3A4/5 inducer is discontinued, the axitinib dose should be immediately restored to the dose used before starting administration of the strong CYP3A4/5 inducer (see Drug Interactions).
4. Special groups of axitinib
Elderly medication: Elderly patients do not need to adjust the dose (see [Elderly Medication] and [Pharmacokinetics]).
Renal Impairment: There have been no trials of axitinib in patients with renal impairment. Based on the results of population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with mild to severe renal impairment (15 mL/min ≤ creatinine clearance [CLcr] < 89 mL/min) (see Pharmacokinetics). No starting dose adjustment of axitinib is required in patients with mild to severe renal impairment. Patients with end-stage renal disease (CLcr <15 mL/min) should use this product with caution.
Hepatic Impairment: When patients with mild hepatic impairment are taking axitinib, no starting dose adjustment is required (Child-Pugh Classification: Level A). Based on pharmacokinetic data, the starting dose of axitinib should be halved when taking axitinib in patients with moderate hepatic impairment at baseline (Child-Pugh Classification: Grade B). Subsequent dosage increases or decreases may be based on individual differences in patient safety and tolerability. Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class: C) and axitinib should not be used in this population (see Precautions and Pharmacokinetics).
Pediatric Population
The safety and efficacy of axitinib have not been studied in pediatric patients [2] .
5. Adverse reactions of axitinib
Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared with the incidence of adverse reactions observed in clinical trials of another drug and may not reflect the incidence of adverse reactions observed in clinical practice.
The safety of axitinib was evaluated in 715 patients in the monotherapy study, including 537 patients with advanced RCC. The data reflect the safety of axitinib in 359 patients with advanced RCC who participated in a randomized clinical study compared with sorafenib (see Clinical Trials).
The following risks, including appropriate measures to be taken (see Precautions), are discussed in more detail in other sections of the labeling: hypertension, arterial thromboembolic events, venous thromboembolic events, bleeding, heart failure, gastrointestinal perforation and fistula formation, thyroid insufficiency, wound healing complications, RPLS, proteinuria, elevated liver enzymes, liver damage and fetal development [2] .
6. Contraindications of axitinib
Allergy to axitinib or any excipients.
7. Inlida Precautions
The following specific safety events should be monitored before starting axitinib treatment and periodically during treatment.
Hypertension and Hypertensive Crisis
In controlled clinical studies of patients with RCC treated with axitinib, hypertension was reported in 145/359 patients (40%) treated with axitinib and 103/355 patients (29%) treated with sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) treated with axitinib and 39/355 patients (11%) treated with sorafenib. Hypertensive crises were reported in 2/359 patients (<1%) treated with axitinib and in no patients treated with sorafenib. Hypertension (systolic blood pressure>The median onset of blood pressure (diastolic blood pressure >150 mmHg, or diastolic blood pressure >100 mmHg) was within 1 month of starting axitinib therapy, and increases in blood pressure were observed as early as 4 days after starting axitinib therapy. High blood pressure can be treated with standard antihypertensive medications. 1/359 patients (<1%) who received axitinib discontinued axitinib treatment due to hypertension, and no patients who received sorafenib discontinued treatment due to hypertension (see [Adverse Reactions]).
Blood pressure should be controlled before starting axitinib treatment. Patients should be monitored for the presence of hypertension and treated with standard antihypertensive medications as needed. If persistent hypertension persists despite treatment with antihypertensive drugs, the dose of axitinib should be reduced. If severe and persistent hypertension occurs despite concomitant administration of antihypertensive agents and a reduced dose of axitinib, axitinib should be discontinued and restarted at a lower dose once the patient becomes normotensive. If evidence of hypertensive crisis occurs, discontinuation of the drug should be considered. If axitinib administration is interrupted, patients receiving antihypertensive agents should be monitored for hypotension (see Dosage and Administration).
Diagnostic brain magnetic resonance imaging should be considered if reversible posterior leukoencephalopathy syndrome (RPLS) (see below), which may be associated with mild to severe hypertension, is suspected.
Arterial Thromboembolic Events
Arterial thromboembolic events, including death, have been reported in clinical trials. In controlled clinical trials in patients with RCC treated with axitinib, grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) treated with axitinib and 4/355 patients (1%) treated with sorafenib. Among 359 patients treated with axitinib, fatal cerebrovascular accident was reported in 1 patient (<1%). No fatal cerebrovascular accidents have been reported in patients receiving sorafenib (see Adverse Reactions).
In clinical trials of axitinib, 17/715 patients (2%) reported arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, retinal artery occlusion), and 2 deaths were secondary to cerebrovascular accidents.
Axitinib should be used with caution in patients who are at risk for, or have a history of, such events. Axitinib has not been studied in patients with an arterial thromboembolic event within the previous 12 months [2] .
Venous thromboembolic events
Venous thromboembolic events, including death, have been reported in clinical trials. In controlled clinical trials of patients receiving axitinib for the treatment of RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving axitinib and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving axitinib (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion, retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 (<1%) patients treated with axitinib and was not reported in patients treated with sorafenib. In clinical trials of axitinib, venous thromboembolic events were reported in 22/715 patients (3%), including 2 deaths secondary to pulmonary embolism.
Axitinib should be used with caution in patients at risk for or with a history of these events. Axitinib has not been studied in patients with a venous thromboembolic event within the previous 6 months.
Hemoglobin or hematocrit increases
An increase in hemoglobin or hematocrit may occur during axitinib treatment, reflecting an increase in the total number of red blood cells (see [Adverse Reactions]). Increased total red blood cell mass may increase the risk of thromboembolic events.
Hemoglobin or hematocrit should be monitored before initiating treatment with axitinib and periodically during treatment. If hemoglobin or hematocrit rises above normal, the patient should be treated routinely to reduce hemoglobin or hematocrit to acceptable levels.
Bleeding
In controlled clinical studies of patients with RCC treated with axitinib, bleeding events were reported in 58/359 patients (16%) treated with axitinib and 64/355 patients (18%) treated with sorafenib. Grade 3/4 bleeding events (including intracerebral hemorrhage, hemoptysis, hematuria, lower gastrointestinal bleeding, and melena) were reported in 5/359 (1%) patients receiving axitinib and 11/355 (3%) patients receiving sorafenib. Fatal bleeding (gastric bleeding) was reported in 1/359 (<1%) patients treated with axitinib and in 3/355 (1%) patients treated with sorafenib.
Axitinib has not been studied in patients with untreated brain metastases or in patients with recent active gastrointestinal bleeding and should not be used in these patients. If a bleeding event requires pharmacological intervention, axitinib administration should be withheld.
Heart failure
In a controlled clinical study of axitinib in patients with RCC, heart failure was reported in 6/359 (2%) patients treated with axitinib and 3/355 patients (1%) treated with sorafenib. Grade 3/4 heart failure was reported in 2/359 (1%) patients treated with axitinib and 1/355 (<1%) patients treated with sorafenib. Fatal heart failure was reported in 2/359 (1%) patients treated with axitinib and in 1/355 (<1%) patients treated with sorafenib.
Monitor for signs or symptoms of heart failure throughout axitinib treatment. It may be necessary to permanently discontinue axitinib to control heart failure.
Gastrointestinal perforation and fistula formation
In a controlled clinical study of RCC patients treated with axitinib, gastrointestinal perforation was reported in 1/359 patients (<1%) treated with axitinib, and no gastrointestinal perforation was reported in patients treated with sorafenib. In clinical trials of axitinib, gastrointestinal perforation was reported in 5/715 patients (1%), including 1 patient death. In addition to patients with gastrointestinal perforation, fistula formation was reported in 4/715 patients (1%).
During axitinib treatment, symptoms of gastrointestinal perforation or fistula formation should be monitored regularly.
Hypothyroidism
In controlled clinical studies in patients with RCC treated with axitinib, hypothyroidism was reported in 69/359 patients (19%) treated with axitinib and 29/355 patients (8%) treated with sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving axitinib and 4/355 patients (1%) receiving sorafenib. Among patients with thyroid-stimulating hormone (TSH) <5 μU/mL before treatment, 79/245 patients (32%) who received axitinib and 25/232 patients (11%) who received sorafenib had TSH elevated to 10 μU/mL or above (see Adverse Reactions).
Thyroid function should be monitored before initiating axitinib treatment and periodically during axitinib treatment. Hypothyroidism and hyperthyroidism should be treated routinely to maintain euthyroid status.
Wound Healing Complications
Formal studies of the effects of axitinib on wound healing have not been conducted.
Axitinib therapy should be discontinued at least 24 hours before scheduled surgery. The timing of restarting axitinib therapy after surgery should be determined based on clinical judgment of whether the wound has completely healed.
Reversible posterior leukoencephalopathy syndrome
In a controlled clinical study of RCC patients treated with axitinib, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) treated with axitinib, and no RPLS was reported in patients treated with sorafenib (see [Adverse Reactions]). Two cases of RPLS were reported in other clinical trials of axitinib.
RPLS is a neurological disorder that may present with headaches, seizures, drowsiness, confusion, blindness, and other visual and neurological disorders. Mild to severe hypertension may also occur. MRI is necessary to confirm the diagnosis of RPLS. Axitinib should be discontinued in patients who develop RPLS. The safety of re-administration of axitinib to patients who have experienced RPLS is unknown.
Proteinuria
In controlled clinical studies of RCC patients treated with axitinib, proteinuria was reported in 39/359 patients (11%) treated with axitinib and 26/355 patients (7%) treated with sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) treated with axitinib and 6/355 patients (2%) treated with sorafenib (see Adverse Reactions).
Urine protein should be monitored before starting axitinib treatment and regularly during axitinib treatment. Patients who develop moderate to severe proteinuria should have axitinib dose reduced or axitinib discontinued.
Elevated liver enzymes
In a controlled clinical study of patients with RCC treated with axitinib, 22% of patients in each treatment group experienced all-grade ALT elevations. Grade 3/4 ALT elevation events occurred in <1% of patients in the axitinib-treated group and 2% of patients in the sorafenib-treated group. The most common liver-related adverse reactions include increases in ALT, AST and blood bilirubin (see [Adverse Reactions]). Simultaneous elevations in ALT (>3 times the upper limit of normal [ULN]) and bilirubin (>2 times ULN) were not observed.
In a clinical dose-finding study, concurrent elevations in ALT (12 times ULN) and bilirubin (2.3 times ULN) were considered drug-related hepatotoxicity and were observed in 1 patient receiving axitinib starting dose of 20 mg twice daily (4 times the recommended starting dose).
ALT, AST, and bilirubin should be monitored before initiating axitinib treatment, and these parameters should be monitored regularly throughout treatment.
Hepatic Impairment
In clinical studies of axitinib, the systemic exposure of axitinib in subjects with moderate hepatic impairment (Child-Pugh class B) was approximately 2 times higher than in subjects with normal liver function. In patients with moderate hepatic impairment (Child-Pugh class B) receiving axitinib, a dose reduction is recommended. Axitinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see Dosage and Administration and Pharmacokinetics) and axitinib should not be used in these patients.
Pregnancy
According to the mechanism of action of axitinib, pregnant women taking axitinib may cause fatal harm to the fetus. There have been no adequate and controlled studies of axitinib in pregnant women. In mouse developmental toxicity studies, axitinib was observed to be teratogenic, embryotoxic, and fetotoxic at maternal exposures below human exposure at clinically recommended doses.
Women of childbearing potential should be advised to use contraception while receiving axitinib. If this product is used during pregnancy, or if a patient receiving this product becomes pregnant, the patient should be informed of the potential hazard to the fetus (see Use in Pregnant and Lactating Women).
Effects on the ability to drive and use machines
Axitinib has a minimal effect on the ability to drive and use machines. Patients should be informed of events that may occur during axitinib treatment such as dizziness and/or fatigue.
8. Medication of Yinlida in special populations
Drug use in pregnant women
There are currently no adequate and controlled studies on the use of axitinib in pregnant women. Based on its mechanism of action, axitinib may cause fetal harm when taken by pregnant women. In mouse developmental toxicity studies, axitinib was observed to be teratogenic, embryotoxic, and fetotoxic at maternal exposures below human exposure at clinically recommended doses. Therefore, patients should be counseled on contraception when considering treatment with axitinib. If this product is used during pregnancy, or if a patient becomes pregnant while receiving this product, the patient should be informed of the potential hazard to the fetus.
When axitinib was administered orally twice daily to female mice prior to mating and during the first week of gestation, increased rates of post-implantation loss were observed in all dose groups tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure [AUC] in patients at the recommended starting dose). In embryo-fetal toxicity studies, pregnant mice received axitinib by gavage at doses of 0.15, 0.5, and 1.5 mg/kg/dose (dose twice daily) during organogenesis. Embryo-fetal toxicity observed in the absence of maternal toxicity included malformation (cleft palate) in the 1.5 mg/kg/dose group (approximately 0.5 times the AUC in patients given the recommended starting dose) and in the ≥0.5 mg/kg/dose group (approximately 0.15 times the AUC obtained in patients given the recommended starting dose), embryo-fetal toxicity observed in the absence of maternal toxicity was abnormal bone calcification.
Use in breast-feeding women
It is unclear whether axitinib is excreted in human milk. Since most drugs are excreted in breast milk, and nursing infants may have serious adverse reactions to axitinib, the importance of the drug to the mother should be considered when deciding whether to terminate breastfeeding or discontinue the drug [2].
Pediatric Use
The safety and effectiveness of axitinib have not been studied in pediatric patients.
Bone and dental toxicity was observed in immature mice and dogs administered oral axitinib BID for 1 month or longer. Skeletal effects including growth plate thickening were observed in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times the systemic exposure [AUC] in patients administered at the recommended starting dose). Abnormalities in the growing incisors (including caries, malocclusion, breakage, and/or missing teeth) were observed in mice dosed twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC obtained in patients at the recommended starting dose). Other potential toxicities in pediatric patients have not been evaluated in young animals [2] .
Geriatric use
In a controlled clinical study of RCC patients treated with axitinib, 123/359 patients (34%) who received axitinib were ≥65 years old. Although higher sensitivity in some older patients cannot be ruled out, overall no differences in the safety and efficacy of axitinib were observed between patients ≥65 years of age and those younger than 65 years of age.
Elderly patients do not need to adjust the dose (see [Dosage and Dosage] and [Pharmacokinetics]) [2] .
9. Inlida drug interactions
In vitro data show that axitinib is mainly metabolized by CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19 and uridine diphosphate-glucuronosyltransferase (UGT) 1A1.
CYP3A4/5 Inhibitors
Ketoconazole is a potent inhibitor of CYP3A4/5. When administered to healthy volunteers at a dose of 400 mg once daily for 7 days, it can increase the average area under the curve (AUC) of a single oral dose of 5 mg axitinib by 2-fold and increase Cmax by 1.5-fold. Coadministration of axitinib with strong CYP3A4/5 inhibitors (such as ketoconazole, itraconazole, clarithromycin, erythromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase axitinib plasma concentrations. It is recommended to choose drugs with no or minimal inhibition potential of CYP3A4/5. If it must be combined with a strong CYP3A4/5 inhibitor, it is recommended to adjust the dose of axitinib (see [Dosage and Administration]).
CYP3A4/5 Inducer
Rifampicin, a potent inducer of CYP3A4/5, reduced the mean AUC of a single 5 mg dose of axitinib by 79% and Cmax by 71% in healthy volunteers at a dose of 600 mg once daily for 9 days.
Coadministration of axitinib with strong CYP3A4/5 inducers (e.g., rifampicin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St. John's wort [also known as St. John's wort]) may decrease axitinib plasma concentrations. It is recommended to choose drugs that have no or minimal potential to induce CYP3A4/5. If it must be used together with a strong CYP3A4/5 inducer, it is recommended to adjust the dose of axitinib (see [Dosage and Administration]).
CYP1A2 and CYP2C19 inhibitors
A small amount (<10%) of axitinib is metabolized by CYP1A2 and CYP2C19. The effect of potent inhibitors of these isoenzymes on axitinib pharmacokinetics has not been studied. Because potent inhibitors of these isoenzymes may increase axitinib plasma concentrations, they should be used with caution.
In vitro studies on CYP and UGT inhibition and induction
In vitro studies indicate that axitinib may inhibit CYP1A2. Therefore, coadministration of axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g., theophylline).
In vitro studies also indicate that axitinib may inhibit CYP2C8. However, coadministration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased paclitaxel plasma concentrations in patients with advanced cancer, suggesting a lack of clinical CYP2C8 inhibition.
In vitro studies in human hepatocytes also indicate that axitinib does not induce CYP1A1, CYP1A2 or CYP3A4/5.
In vitro studies on P-glycoprotein
In vitro studies show that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Coadministration with axitinib is therefore not expected to increase plasma concentrations of digoxin or other P-glycoprotein substrates.
10. Inlida overdose
There is no treatment for axitinib overdose.
In a controlled clinical study of RCC patients receiving axitinib, 1 patient accidentally received a dose of 20 mg twice daily for 4 days and developed dizziness (Grade 1).
In a clinical dose-finding study of axitinib, adverse reactions in subjects who received a starting dose of 10 mg BID or 20 mg BID included hypertension, hypertension-related seizures, and fatal hemoptysis.
In case of suspected overdose, axitinib should be discontinued and supportive treatment should be given [2].
11. Pharmacology and Toxicology of Yinglida
Pharmacological effects
Axitinib can inhibit tyrosine kinase receptors, including vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2 and VEGFR-3) at therapeutic doses. These receptors are associated with pathological angiogenesis, tumor growth, and cancer progression. In vitro experiments and in vivo mouse model experiments show that axitinib can inhibit VEGF-mediated endothelial cell proliferation and survival; in tumor-bearing mouse models, axitinib can inhibit tumor growth and phosphorylation of VEGFR-2 [2].
Toxicological studies
Genotoxicity: The results of axitinib Ames test and human lymphocyte chromosomal aberration test were negative, and the results of mouse bone marrow micronucleus test were positive.
Reproductive toxicity: Axitinib may damage human reproductive function and fertility. In repeated dose toxicity tests, oral administration of ≥15 mg/kg/dose to mice 2 times/day (approximately 7 times the systemic exposure (AUC) at the recommended starting dose for humans), or oral administration to dogs 2 times/day at ≥1.5 mg/kg/dose (approximately 0.1 times the systemic exposure at the recommended starting dose for humans), can cause testicular/epididymis weight reduction, atrophy or degeneration, reduced germinal cell number, sperm count or abnormal sperm formation, and reduced sperm density or count in male animals; at ≥5 Reproductive tract abnormalities were seen in female mice and female dogs at mg/kg/dose (1.5 times or 0.3 times the systemic exposure at the recommended human starting dose in rats and dogs respectively), including delayed sexual maturation, reduced or absent corpus luteum, reduced uterine weight, and uterine atrophy.
In the mouse fertility test, male mice were orally administered 2 times/day for at least 70 days. Axitinib 50 mg/kg/dose (approximately 57 times the systemic exposure at the recommended starting dose for humans) had no effect on the mating rate and fertility rate of male mice. Oral administration to female mice 2 times/day for at least 15 days, ≥15mg/kg/dose (approximately 10 times the systemic exposure at the recommended starting dose for humans) can cause reduced fertility and embryonic survival rate in female mice.
In embryo-fetal toxicity studies, pregnant mice were orally administered axitinib during organogenesis at doses of 0.15, 0.5, and 1.5 mg/kg, twice a day. Embryo-fetal toxicity, including malformations (cleft palate), was seen at a dose of 1.5 mg/kg (approximately 0.5 times the systemic exposure at the recommended starting dose in humans); abnormal bone calcification was seen at a dose ≥ 0.5 mg/kg (approximately 0.15 times the systemic exposure at the recommended starting dose in humans) [2].
12. Inlida Pharmacokinetics
The population pharmacokinetic analysis summarizes data from 17 trials completed in healthy subjects and cancer patients. The concentration-time profile of axitinib was adequately described using a two-compartment model with first-order absorption and lag time.
Absorption and Distribution: After a single oral dose of 5 mg, the median Tmax range is 2.5 to 4.1 hours. Based on the plasma half-life, it is expected to reach steady state within 2 to 3 days after administration. Axitinib administered twice daily at 5 mg resulted in approximately 1.4-fold accumulation of the drug compared with single administration. At steady state, axitinib exhibits linear pharmacokinetics in the dose range of 1 mg to 20 mg. The mean absolute bioavailability of axitinib after an oral 5 mg dose was 58%.
Compared with taking axitinib overnight on an empty stomach, axitinib was taken with a moderate-fat meal, resulting in a 10% decrease in AUC, while administration with a high-fat, high-calorie meal resulted in a 19% increase in AUC. Axitinib can be taken with food or on an empty stomach (see [Dosage and Administration]).
Axitinib is highly bound to human plasma proteins (>99%), preferentially binding to albumin, and has a moderate binding rate to α1-acid globulin. In patients with advanced RCC (n=20), the geometric mean (CV%) Cmax and AUC0-24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively, given twice daily 5 mg doses in the fed state. The geometric mean values (CV%) of clearance rate and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L respectively.
Metabolism and excretion: The plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Axitinib is mainly metabolized by liver CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. When axitinib was administered orally at a radioactive dose of 5 mg, approximately 41% of the radioactivity was recovered in the feces and 23% of the radioactivity was recovered in the urine.
Axitinib parent drug (accounting for 12% of the administered dose) was the main component identified in the feces; carboxylic acid metabolites and sulfoxide metabolites accounted for the vast majority of radioactivity in the urine. In plasma, N-glucuronide metabolites represent the major radioactive component (accounting for 50% of circulating radioactivity), with axitinib parent drug and sulfoxide metabolites each accounting for 20% of circulating radioactivity.
Compared with axitinib, the in vitro potency of sulfoxide metabolites and N-glucuronic acid metabolites on VEGFR-2 is reduced by 400 times or more [2].
13. Pharmacokinetics of Yinglida in special populations
Pediatric use: Axitinib has not been studied in patients under 18 years of age.
Liver damage: The impact of liver damage on the pharmacokinetics of axitinib is shown in Figure 4 (see [Dosage and Dosage] and [Precautions]).
Renal Impairment: Population pharmacokinetic analyzes (based on pre-existing renal function) were completed in 590 healthy volunteers and patients, including 5 patients with severe renal impairment (15 mL/min ≤CLcr<29 mL/min), 64 patients with moderate renal impairment (30 mL/min≤CLcr <59 mL/min), and 139 patients with mild renal impairment (60 mL/min≤CLcr <89 mL/min). Mild to severe renal impairment has no meaningful effect on axitinib pharmacokinetics. Data are available from only one patient with end-stage renal disease (see [Usage and Dosage]).
Other intrinsic factors: Population pharmacokinetic analysis results show that patient age, race, weight, body surface area, UGT1A1 genotype or CYP2C19 genotype have no clinically relevant impact on the clearance rate of axitinib [2].