Clinical Pharmacology of Axitinib

Abstract

Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5 mg twice daily, taken with or without food. Dose increase (up to a maximum of 10 mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20 mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1 h), and the plasma accumulation of axitinib is in agreement with what is expected based on the plasma half-life of the drug. Axitinib is absorbed relatively rapidly, reaching maximum observed plasma concentrations (C max) within 4 h of oral administration. The mean absolute bioavailability of axitinib is 58 %. Axitinib is highly (>99 %) bound to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced renal cell carcinoma, at the 5-mg twice-daily dose in the fed state, the geometric mean (% coefficient of variation) C max and area under the plasma concentration-time curve (AUC) from time 0-24 h (AUC24) were 27.8 ng/mL (79 %) and 265 ng·h/mL (77 %), respectively. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10 % each), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. The two major human plasma metabolites, M12 (sulfoxide product) and M7 (glucuronide product), are considered pharmacologically inactive. Axitinib is eliminated via hepatobiliary excretion with negligible urinary excretion. Although mild hepatic impairment does not affect axitinib plasma exposures compared with subjects with normal hepatic function, there was a 2-fold increase in AUC from time zero to infinity (AUC∞) following a single 5-mg dose in subjects with moderate hepatic impairment. In the presence of ketoconazole, a strong CYP3A4/5 inhibitor, axitinib C max and AUC∞ increased by 1.5- and 2-fold, respectively, whereas co-administration of rifampin, a strong CYP3A4/5 inducer, resulted in a 71 and 79 % decrease in the C max and AUC∞, respectively. Axitinib does not inhibit CYP3A4/5, CYP1A2, CYP2C8, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or UGT1A1 at concentrations obtained with the clinical doses and is not expected to have major interactions with drugs that are metabolized by these enzymes. Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro, but is not expected to inhibit P-gp at therapeutic plasma concentrations. A two-compartment population pharmacokinetic model with first-order absorption and lag time was used to describe axitinib pharmacokinetics. No clinically relevant effects of age, sex, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 inferred phenotype on the clearanc...

In Vitro Kinetic Characterization of Axitinib Metabolism

“…The formation of M7 in HLMs displayed a high-affinity (low K m ) process as opposed to the low-affinity formation of Glu3, exhibiting a 33-fold lower CL int than those derived from M7 formation. Since the peak axitinib exposure in humans is low (C max 0.072 mM or 0.36 nM free) (Chen et al, 2013), these in vitro data provide an explanation as to why at low exposures of axitinib, M7 would be the glucuronide with the highest formation rate and thus be detected in human plasma and excreta. When comparing the axitinib kinetic parameters using HLMs for both the sulfoxide and glucuronidation and taking into account the recombinant enzymes, it was apparent that the sulfoxide metabolite accounts for a major portion of axitinib metabolism, and the glucuronidation pathway contributes only a nominal portion toward the total metabolic clearance of axitinib (Tables 1 and 3).…”

“…The major in vitro oxidative metabolite of axitinib is the sulfoxide (M12) and was also identified as a significant circulating metabolite representing 16.2% of radioactivity in vivo in humans and a notable metabolite eliminated in urine (Chen et al, 2013). In general, sulfoxidation can be mediated by both P450s and FMOs.…”

“…Clinical drug interaction studies with axitinib as an object or victim drug have been conducted in combination with ketoconazole and rifampin as strong inhibitors and inducers, respectively, of CYP3A and the respective changes in axitinib plasma exposure suggested a predominant role for CYP3A in the clearance of axitinib since ketoconazole increased the area under the plasma versus time curve (AUC) ratio relative to control by 2.1-fold and rifampin pretreatment decreased this AUC ratio to 0.21 (Pithavala et al, 2010. The axitinib plasma exposure in cancer patients is variable (e.g., interindividual variability expressed as %CV is on the order of ;80%), but has been effectively addressed in the clinic by use of a dose-tolerability titration schedule that essentially normalizes patient exposure over a dose range from 2 to 20 mg/day [Pfizer Laboratories, 2012, prescribing information for Inlyta (axitinib) tablets for oral administration] (Chen et al, 2013;Rini et al, 2013). Therefore, better understanding of the factors that contribute to axitinib exposure variability could impact therapy through identification of factors that could be used to predict dose prior to initiation of drug treatment.…”

Individualized Dosing with Axitinib: Rationale and Practical Guidance

“…Co-administration of axitinib with agents known to be strong CYP3A4/5 inhibitors (e.g., ketoconazole and clarithromycin) or inducers (e.g., phenytoin, dexamethasone, rifampicin and St John's wort) may cause axitinib plasma concentrations to increase or decrease, respectively [26]. Furthermore, for self-administered, oral regimens, compliance is an essential factor in determining efficacy.…”

Drug Interactions in Palliative Cancer Care and Oncology

“…Of interest in the palliative care setting, the CYP3A4-specifi c probe that was utilized was midazolam, suggesting that pazopanib has the potential to decrease the clearance of midazolam. Clinically meaningful interactions as a result of CYP enzyme inhibition/induction by axitinib have not been demonstrated (Chen et al 2013 ).…”