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Mechanism Of Action
Axitinib has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell proliferation and survival were inhibited by axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.
The effect of a single oral dose of INLYTA (5 mg) in the absence and presence of 400 mg ketoconazole on the QTc interval was evaluated in a randomized, single-blinded, two-way crossover study in 35 healthy subjects. No large changes in mean QTc interval (i.e., > 20 ms) from placebo were detected up to 3 hours post-dose. However, small increases in mean QTc interval (i.e., < 10 ms) cannot be ruled out.
The population pharmacokinetic analysis pooled data from 17 trials in healthy subjects and patients with cancer. A two-compartment disposition model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile.
Absorption and Distribution
Following single oral 5-mg dose administration, the median Tmax ranged from 2.5 to 4.1 hours. Based on the plasma half-life, steady state is expected within 2 to 3 days of dosing. Dosing of axitinib at 5 mg twice daily resulted in approximately 1.4-fold accumulation compared to administration of a single dose. At steady state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose range. The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.
Compared to overnight fasting, administration of INLYTA with a moderate fat meal resulted in 10% lower AUC and a high fat, high-calorie meal resulted in 19% higher AUC. INLYTA can be administered with or without food [see DOSAGE AND ADMINISTRATION].
Axitinib is highly bound ( > 99%) to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced RCC (n=20), at the 5 mg twice daily dose in the fed state, the geometric mean (CV%) C max and AUC 0-24 were 27.8 (79%) ng/mL and 265 (77%) ng.h/mL, respectively. The geometric mean (CV%) clearance and apparent volume of distribution were 38 (80%) L/h and 160 (105%) L, respectively.
Metabolism and Elimination
The plasma half life of INLYTA ranges from 2.5 to 6.1 hours. 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, approximately 41% of the radioactivity was recovered in feces and approximately 23% 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 less in vitro potency against VEGFR-2 compared to axitinib.
Effects of Other Drugs on INLYTA: Axitinib is metabolized primarily in the liver by CYP3A4/5. Additionally, the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility. The effects of a strong CYP3A4/5 inhibitor, a strong CYP3A4/5 inducer, and an antacid on the pharmacokinetics of axitinib are presented in Figure 1 [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
Figure 1 : Impact of Co-administered Drugs and Hepatic
Impairment on Axitinib Pharmacokinetics
AUC: Area under the curve. Cmax: Maximum concentration. See DOSAGE AND ADMINISTRATION.
Effects of INLYTA on Other Drugs: In vitro studies demonstrated that axitinib has the potential to inhibit CYP1A2 and CYP2C8. However, co-administration of axitinib with paclitaxel, a CYP2C8 substrate, did not increase plasma concentrations of paclitaxel in patients.
In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1 at therapeutic plasma concentrations. In vitro studies in human hepatocytes indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5.
Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro. However, INLYTA is not expected to inhibit P-gp at therapeutic plasma concentrations.
Pharmacokinetics in Specific Populations
Pediatric Use: INLYTA has not been studied in patients < 18 years of age.
Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of axitinib are presented in Figure 1 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and Use in Specific Populations].
Renal Impairment: Population pharmacokinetic analysis (based on pre-existing renal function) was carried out in 590 healthy volunteers and patients, including five with severe renal impairment (15 mL/min ≤ CLcr < 29 mL/min), 64 with moderate renal impairment (30 mL/min ≤ CLcr < 59 mL/min), and 139 with mild renal impairment (60 mL/min ≤ CLcr < 89 mL/min). Mild to severe renal impairment did not have meaningful effects on the pharmacokinetics of axitinib. Data from only one patient with end-stage renal disease are available [see Use in Specific Populations].
Other Intrinsic Factors: Population pharmacokinetic analyses indicate that there are no clinically relevant effects of age, gender, race, body weight, body surface area, UGT1A1 genotype, or CYP2C19 genotype on the clearance of axitinib.
The safety and efficacy of INLYTA 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 INLYTA (N=361) or sorafenib (N=362). Progression-free survival (PFS) was assessed by a blinded independent central review committee. Other 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 INLYTA and sorafenib groups with regard to age (median 61 years), gender (72% male), race (75% white, 21% Asian), Eastern Cooperative Oncology Group (ECOG) performance status (55% 0, 45% 1), and histology (99% clear cell).
There was a statistically significant advantage for INLYTA over sorafenib for the endpoint of PFS (see Table 3 and Figure 2). There was no statistically significant difference between the arms in OS.
Table 3: Efficacy Results
|Endpoint/Study Population||INLYTA||Sorafenib||HR (95% CI)||P-value|
|Overall ITT||N= 361||N = 362|
|Median PFSa,b in months (95% CI)||6.7 (6.3, 8.6)||4.7 (4.6, 5.6)||0.67 (0.54, 0.81)||< 0.0001c|
|Median OS in months (95% CI)||20.1 (16.7, 23.4)||19.2 (17.5, 22.3)||0.97 (0.80, 1.17)||NS|
|ORR % (95% CI)||19.4 (15.4, 23.9)||9.4 (6.6, 12.9)||2.06d (1.41, 3.00)||-e|
|PFS by prior treatment|
|Median, months (95% CI)||4.8 (4.5, 6.4)||3.4 (2.8, 4.7)||0.74 (0.57, 0.96)||-e|
|Median, months (95% CI)||12.1 (10.1, 13.9)||6.5 (6.3, 8.3)||0.46 (0.32, 0.68)||-e|
|CI: Confidence interval; HR:
Hazard ratio (INLYTA/sorafenib); ITT: Intent to treat; ORR: Objective response
rate; NS: Not significant; OS: Overall survival; PFS: Progression-free survival
aTime from randomization to progression or death due to any cause, whichever occurs first.
bAssessed by independent radiology review according to RECIST.
cOne-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy (comparison is considered statistically significant if the one-sided p-value is < 0.023).
dRisk ratio is used for ORR. A risk ratio > 1 indicated a higher likelihood of responding in the axitinib arm; a risk ratio < 1 indicated a higher likelihood of responding in the sorafenib arm.
eP-value not included since it was not adjusted for multiple testing.
Figure 2: Kaplan-Meier Curve for Progression Free
Survival by Independent Assessment (Intent-to-Treat Population)
Last reviewed on RxList: 8/15/2014
This monograph has been modified to include the generic and brand name in many instances.
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