Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers

Pithavala, Yazdi K.; Chen, Ying; Toh, Melvin; Selaru, Paulina; LaBadie, Robert R.; Garrett, May; Hee, Brian; Mount, Janessa; Ni, Grace; Klamerus, Karen J.; Tortorici, Michael A.

doi:10.1007/s00280-012-1888-9

Cited by 41 publications

(21 citation statements)

References 17 publications

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“…We confirmed that all subjects received the entire dose by counting the radioactivity before and after administration. Further, the plasma axitinib C max and AUC presented in Table 1 was similar to what has been observed in other studies involving healthy human subjects receiving the same 5-mg single oral dose of the drug (Pithavala et al, 2010(Pithavala et al, , 2012a. The recovery of radiolabeled axitinib equivalents in urine was consistent between subjects, and the urinary excretion rate was similar and aligned with the plasma pharmacokinetics of total radioactivity and parent drug.…”

Section: Discussionsupporting

confidence: 65%

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Smith

Pithavala

et al. 2014

Drug Metabolism and Disposition

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The disposition of a single oral dose of 5 mg (100 mCi) of [ 14 C]axitinib was investigated in fasted healthy human subjects (N = 8). Axitinib was rapidly absorbed, with a median plasma T max of 2.2 hours and a geometric mean C max and half-life of 29.2 ng/ml and 10.6 hours, respectively. The plasma total radioactivity-time profile was similar to that of axitinib but the AUC was greater, suggesting the presence of metabolites. The major metabolites in human plasma (0-12 hours), identified as axitinib N-glucuronide (M7) and axitinib sulfoxide (M12), were pharmacologically inactive, and with axitinib comprised 50.4%, 16.2%, and 22.5% of the radioactivity, respectively. In excreta, the majority of radioactivity was recovered in most subjects by 48 hours postdose. The median radioactivity excreted in urine, feces, and total recovery was 22.7%, 37.0%, and 59.7%, respectively. The recovery from feces was variable across subjects (range, 2.5%-60.2%). The metabolites identified in urine were M5 (carboxylic acid), M12 (sulfoxide), M7 (N-glucuronide), M9 (sulfoxide/N-oxide), and M8a (methylhydroxy glucuronide), accounting for 5.7%, 3.5%, 2.6%, 1.7%, and 1.3% of the dose, respectively. The drug-related products identified in feces were unchanged axitinib, M14/15 (mono-oxidation/sulfone), M12a (epoxide), and an unidentified metabolite, comprising 12%, 5.7%, 5.1%, and 5.0% of the dose, respectively. The proposed mechanism to form M5 involved a carbon-carbon bond cleavage via M12a, followed by rearrangement to a ketone intermediate and subsequent Baeyer-Villiger rearrangement, possibly through a peroxide intermediate. In summary, the study characterized axitinib metabolites in circulation and primary elimination pathways of the drug, which were mainly oxidative in nature.

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Section: Discussionsupporting

confidence: 65%

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Smith

Pithavala

et al. 2014

Drug Metabolism and Disposition

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“…Inter-subject variability in plasma exposure has been noted following axitinib doses in healthy volunteers [13] and in cancer patients [11], similar to that observed with other orally administered antiangiogenic tyrosine kinase inhibitors, such as sorafenib [14] and sunitinib [15]. This variation in axitinib pharmacokinetics could contribute to the variability in clinical efficacy, as well as to the incidence of adverse events observed in patients treated with axitinib and other antiangiogenic agents that act through the VEGF/VEGFR signalling pathways.…”

Section: Introductionmentioning

confidence: 84%

Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

Brennan

Chen

et al. 2011

Eur J Clin Pharmacol

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Purpose Axitinib, an orally administered inhibitor of vascular endothelial growth factor 1, 2 and 3, is primarily metabolized by cytochrome P450 (CYP) 3A4/5 but is also a substrate for CYP1A2, CYP2C19, UDP-glucuronosyltransferase (UGT) 1A1 and the drug transporters P-glycoprotein (encoded by the ABCB1 gene) and OATP1B1 (encoded by SLC01B1). The potential contribution of polymorphisms in genes encoding these enzymes and transporters to axitinib pharmacokinetic variability was assessed. Methods A fixed effects meta-analysis was performed using data pooled from 11 healthy volunteer clinical pharmacology trials to investigate the potential association between axitinib exposure and major polymorphisms in these genes following a 5-mg dose of axitinib.Results Up to 15 variant alleles were evaluated and up to 315 healthy volunteers per polymorphism were assayed. None of the polymorphisms analysed was a statistically significant predictor of axitinib pharmacokinetic variability. Amongst genotypes and inferred phenotypes, CYP2C19 genotype and the ABCB1 (G2677T/A) polymorphism were the closest to statistical significance in influencing axitinib pharmacokinetic variability after multiple-testing adjustment. However, no enzyme or transporter genotype/inferred phenotype contributed >5% to the overall pharmacokinetic variability of axitinib. Conclusions No statistically significant associations between the specific polymorphisms analysed and axitinib plasma exposure were observed, suggesting that genotype-or inferred phenotype-based adjustment of axitinib dose in individual subjects is not warranted.

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“…The food effect on Form XLI could not be tested in this analysis since data from the study measuring plasma PK for Form XLI administered with food vs. after fasting were not available at the time of this analysis. Recently, however, results of the food effect study directly comparing the two crystal polymorph formulations showed that the food effect was not clinically meaningful for Form XLI [15]. Hence, the recommendation is that axitinib can be taken with or without food.…”

Section: Discussionmentioning

confidence: 99%

“…Axitinib PK following a single dose have been studied in more than 500 healthy volunteers [13][14][15][16][17][18] and approximately 90 patients with advanced solid tumours [11,[19][20][21][22]. As seen with other orally administered drugs, including tyrosine kinase inhibitors [23][24][25], axitinib PK were variable in healthy volunteers as well as in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic analysis of axitinib in healthy volunteers

Garrett

Poland²,

Brennan

et al. 2014

Br J Clin Pharmacol

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AIMSAxitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODSPlasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (NONMEM) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTSA two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc), absorption rate constant (ka) and absolute bioavailability (F) were 17.0 l h −1 , 45.3 l, 0.523 h −1 and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc, but the effect was within the estimated interindividual variability for Vc. CONCLUSIONSThe analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3.• It has demonstrated superior efficacy over sorafenib in a randomized phase III clinical trial in patients with metastatic renal cell carcinoma (mRCC), whose disease progressed following one prior first line systemic therapy. WHAT THIS STUDY ADDS• A population pharmacokinetic model was developed and the effects of various demographics, measures of renal and hepatic function and genetic factors on axitinib disposition were evaluated in healthy volunteers in the absence of confounding factors that are often associated with cancer patients.• Of the covariates tested, body weight was found to affect significantly interindividual variability in axitinib pharmacokinetics.• The model developed here is useful in assessing the impact of other factors on axitinib plasma exposure.

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Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers

Abstract: While axitinib Form IV FCIR was associated with higher plasma exposure after overnight fasting, axitinib Form XLI FCIR can be administered with or without food as differences in axitinib pharmacokinetics under the two conditions were not clinically meaningful.

Cited by 41 publications

References 17 publications

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Pharmacokinetics, Metabolism, and Excretion of [14C]Axitinib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Humans

Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics

Population pharmacokinetic analysis of axitinib in healthy volunteers

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