Pharmacokinetics Of Axitinib Research Articles

Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers

Summary Objective Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole. Methods In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days). Results Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration–time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84–2.30) and a geometric mean ratio for maximum plasma concentration (Cmax) of 1.50 (90% CI: 1.33–1.70). For axitinib alone or with ketoconazole, Cmax occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea. Conclusions Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition.

273 Effect of food on the pharmacokinetics (PK) of axitinib in healthy volunteers (HVs)

273 Effect of food on the pharmacokinetics (PK) of axitinib in healthy volunteers (HVs)

Abstract 2762: An open-label phase 1 study to evaluate the pharmacokinetics of axitinib (AG-013736) in healthy Chinese volunteers

Abstract Introduction: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is mainly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP1A2, CYP2C19, and uridine glucuronyltransferase (UGT1A1). Axitinib currently is in Phase 3 development for renal cell carcinoma. As part of the global clinical development program for axitinib, studies are ongoing in cancer patients in China. A clinical assessment of axitinib pharmacokinetics in healthy Chinese subjects, including dose-proportionality, was conducted to support the regulatory submission in China. Methods: This was an open-label, fixed-sequence study conducted in mainland China in 14 healthy volunteers. All subjects received a single axitinib dose of 5 mg, 7 mg, and 10 mg under fed conditions in study periods 1, 2, and 3, respectively, followed by safety and pharmacokinetic monitoring. Each study period was separated by a washout period of at least 7 days between successive axitinib doses. Serial blood sampling for axitinib pharmacokinetics was performed up to 32 hours postdose in each period. Plasma concentrations of axitinib were measured using a validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) method. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Results: Axitinib AUC0-∞ (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) estimates in healthy Chinese volunteers in this study are reported here. The geometric mean estimate of AUC0-∞ was 150, 251, and 321 ng[[Unable to Display Character: ∙]]h/mL for doses of 5 mg, 7 mg, and 10 mg, respectively. This represented AUC0-∞ increments of 1:1.7:2.1 for dose increments of 1:1.4:2, respectively (ie, a proportional increase in AUC0-∞ per dose increment). Similarly, the geometric mean estimate of Cmax was 33.5, 51.1, and 69.4 ng/mL for 5 mg, 7 mg, and 10 mg, respectively, representing Cmax increments of 1:1.5:2.1 for dose increments of 1:1.4:2, respectively (a proportional increase in Cmax per dose increment). Axitinib was well tolerated with no serious adverse events (AEs) or discontinuations; the only observed AE was mild abdominal distension in 1 subject. Conclusions:. Dose-proportional linear pharmacokinetics for axitinib were observed for the 5 mg to 10 mg dose range in this study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2762.

Axitinib (AG-013736) in combination with FOLFOX and bevacizumab (Bev) in patients (pts) with metastatic solid tumors: A phase I study

4112 Background: Axitinib is an oral, potent and selective inhibitor of VEGF receptors 1, 2, and 3 that is being assessed in a broad range of tumors. This phase I portion of the study evaluated the safety and pharmacokinetics (PK) of axitinib in combination with BV and FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin) in pts with previously treated gastrointestinal and solid tumors. Methods: Pts in cohort 1 received BV 1 mg/kg, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 bolus then 2,400 mg/m2 by 46–48 h infusion, and axitinib at a starting dose of 5 mg PO BID. BV and FOLFOX were administered once every 2 weeks. Following demonstration of tolerability to BV 1 mg/kg in cohort 1, BV was escalated to doses of 2 mg/kg and 5 mg/kg in cohorts 2 and 3 respectively. Patients were evaluated for potential PK interactions between BV, FOLFOX, and axitinib. Safety and tumor response were also assessed. Results: Among pts enrolled in cohorts 1, 2, and 3 (n=15), 2 patients (13%) showed a partial response and 9 patients (60%) exhibited stable disease. The most frequently reported, treatment-emergent grade 3–5 adverse events were neutropenia (n=3), hypertension (n=3), and dyspnea (n=2). PK parameters and plasma profiles of BV, oxaliplatin, and 5-FU were similar in the presence or absence of axitinib, with mean (%CV) AUCinf for platinum clearance from ultrafiltrate of 7,155 ng.h/mL (74%) and 7,702 ng.h/mL (72%), respectively (n=14). Axitinib PK profiles were similar in the presence or absence of BV/FOLFOX. Conclusions: PK data indicate no evidence of an interaction between axitinib and BV/FOLFOX. Axitinib 5 mg BID in combination with BV 1 mg/kg or 2 mg/kg and FOLFOX was well tolerated. Tolerability data for combination treatment with the 5 mg BV dose await completion of patient enrollment into cohort 3. A 3-arm, randomized phase II study of axitinib/FOLFOX vs BV/FOLFOX vs axitinib/BV/FOLFOX in pts with metastatic colorectal cancer has been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer