Pharmacology: Pharmacodynamics: Mechanism of action:
Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumor vasculature that expressed the target in vivo
and produced tumor growth delay, regression, and inhibition of metastases in many experimental models of cancer.
In a randomized, 2-way crossover study, 35 healthy subjects were administered a single oral dose of axitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that axitinib plasma exposures up to 2-fold greater than the therapeutic levels expected following a 5 mg dose did not produce clinically-significant QT interval prolongation.
The safety and efficacy of axitinib were evaluated in a randomized, open-label, multicenter Phase 3 study. Patients (N=723) with advanced RCC whose disease had progressed on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens were randomized (1:1) to receive axitinib (n=361) or sorafenib (n=362). The primary endpoint, progression-free survival (PFS), was assessed using a blinded independent central review. Secondary endpoints included objective response rate (ORR) and overall survival (OS).
Of the patients enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251 patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or interferon-alfa), 59 patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had received 1 prior temsirolimus-based therapy. The baseline demographic and disease characteristics were similar between the axitinib and sorafenib groups with regard to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment.
There was a statistically significant advantage for axitinib over sorafenib for the primary endpoint of PFS (see Table 1 and Figure 1). There was no statistically significant difference between the arms in OS.
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Click on icon to see table/diagram/image
After oral administration of axitinib tablets, the mean absolute bioavailability is 58% compared to intravenous administration. The plasma half-life of axitinib ranges from 2.5 to 6.1 hours. Dosing of axitinib at 5 mg twice daily resulted in <2-fold accumulation compared to administration of a single dose. Based on the short half-life of axitinib, steady state is expected within 2 to 3 days of the initial dose.
Absorption and distribution:
Peak axitinib concentrations in plasma are generally reached within 4 hours following oral administration of axitinib with the median Tmax
ranging from 2.5 to 4.1 hours. Administration of axitinib with a moderate fat meal resulted in 10% lower exposure compared to overnight fasting. A high fat, high-calorie meal resulted in 19% higher exposure compared to overnight fasting. Axitinib may be administered with or without food.
The average Cmax
and AUC increased proportionally over an axitinib dosing range of 5 to 10 mg. In vitro
binding of axitinib to human plasma proteins is >99% with preferential binding to albumin and moderate binding to α1
-acid glycoprotein. At the 5 mg twice daily dose in the fed state, the geometric mean peak plasma concentration and 24-hour AUC were 27.8 ng/mL and 265 ng.h/mL, respectively, in patients with advanced RCC. The geometric mean oral clearance and apparent volume of distribution were 38 L/h and 160 L, respectively.
Metabolism and elimination:
Axitinib is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Following oral administration of a 5-mg radioactive dose of axitinib, 30-60% of the radioactivity was recovered in feces and 23% of the radioactivity was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in feces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine. In plasma, the N-glucuronide metabolite represented the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.
The sulfoxide and N-glucuronide metabolites show approximately 400-fold and 8000-fold less in vitro
potency, respectively, against VEGFR-2 compared to axitinib.
Gender, race, and age: Population pharmacokinetic analyses in patients with advanced cancer (including advanced RCC) and healthy volunteers indicate that there are no clinically relevant effects of age, gender, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 genotype.
Pediatric population: Axitinib has not been studied in patients <18 years of age.
Hepatic impairment: In vitro
and in vivo
data indicate that axitinib is primarily metabolized by the liver. Compared to subjects with normal hepatic function, systemic exposure following a single dose of axitinib was similar in subjects with mild hepatic impairment (Child-Pugh class A) and higher (approximately 2-fold) in subjects with moderate hepatic impairment (Child-Pugh class B). Axitinib has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).
Renal impairment: Unchanged axitinib is not detected in the urine.
Axitinib has not been studied in subjects with renal impairment. In clinical studies with axitinib for the treatment of patients with RCC, patients with serum creatinine >1.5 times the ULN or calculated creatinine clearance <60 mL/min were excluded.
Population pharmacokinetic analyses have shown that axitinib clearance was not altered in subjects with renal impairment and no dose adjustment of axitinib is required.
Toxicology: Preclinical safety data:
Carcinogenicity: Carcinogenicity studies have not been performed with axitinib.
Genotoxicity: Axitinib was tested using a series of genetic toxicology assays consisting of in vitro
bacterial reverse mutation (Ames), human lymphocyte chromosome aberration, and in vivo
mouse bone marrow micronucleus assays. Axitinib was not mutagenic or clastogenic in these assays.
Impairment of fertility: Axitinib has the potential to impair reproductive function and fertility in humans. Findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms) at ≥100 mg/kg/day in mice (approximately 306 times the AUC at the recommended starting dose in humans) and ≥3 mg/kg/day in dogs (approximately 0.5 times the AUC at the recommended starting dose in humans). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥10 mg/kg/day (approximately equivalent to the AUC at the recommended starting dose in humans).
Axitinib did not affect mating or fertility in male mice at any dose tested up to 100 mg/kg/day. However, reduced testicular weights, sperm density and count were noted at ≥30 mg/kg/day (approximately 72 times the AUC at the recommended starting dose in humans) following at least 70 days of treatment with axitinib. No adverse male reproductive effects in mice were noted at 10 mg/kg/day (approximately 21 times the AUC at the recommended starting dose in humans). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥30 mg/kg/day) following at least 15 days of treatment with axitinib (approximately 64 times the AUC at the recommended starting dose in humans).
Developmental toxicity: Pregnant mice exposed to axitinib at an oral dose level of 3 mg/kg/day (approximately 3 times the AUC at the recommended starting dose in humans), showed an increased occurrence of cleft palate and common variations in skeletal ossification. No fetal alterations were observed in mice at a dose level of 1 mg/kg/day (approximately equivalent to the AUC at the recommended starting dose in humans).
Toxicity studies in juvenile animals: Physeal dysplasia was observed in immature mice and dogs given axitinib at doses of ≥30 mg/kg/day for at least 1 month (approximately 37 times the AUC at the recommended starting dose in humans); the incidence and severity were dose-related and the effects were reversible when treatment stopped. Dental caries were observed in mice treated for more than 1 month at axitinib doses of ≥10 mg/kg/day (approximately 9 times the AUC at the recommended starting dose in humans); residual findings, indicative of partial reversibility, were observed when treatment stopped. For physeal dysplasia, no effect levels of 10 mg/kg/day in mice (approximately 8 times the AUC at the recommended starting dose in humans) and 10 mg/kg/day in dogs (approximately equivalent to the AUC at the recommended starting dose in humans) were determined in animals given axitinib for 1 month. A no effect level was not defined for caries of the incisors in mice. Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.