Pharmacokinetics Of Axitinib Research Articles

Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma.

Purpose Axitinib is an orally active multikinase inhibitor currently used to treat patients with metastatic renal cell carcinoma (RCC). This study examined the pharmacokinetics of axitinib and the relationship between peak drug concentration (Cmax) and clinical outcomes in real-world practice. Methods Twenty patients with metastatic RCC treated with axitinib monotherapy were enrolled. Post-dose (1-4h) blood samples were obtained, and axitinib Cmax in plasma was measured by liquid chromatography-tandem mass spectrometry. Efficacy endpoints were best overall response (per RECIST 1.1) and progression-free survival (PFS). The safety endpoint was the cumulative incidence of dose-limiting toxicities (DLTs). Results Large inter- and intra-individual variability in dose-adjusted Cmax was observed (0.02-11.2ng/mL/mg). Axitinib absorption was significantly influenced by glucuronidation activity (P = 0.040). Cmax at steady state was significantly higher in responders than in non-responders (P = 0.013). The optimal Cmax cutoff to predict a clinical response was 12.4ng/mL. The median PFS was significantly longer in patients who achieved an average steady state Cmax above the threshold than in those who did not (799 vs. 336days; P = 0.047). The cumulative incidence of DLTs was significantly higher in patients with Cmax ≥ 40.2ng/mL than in other patients (sub-hazard ratio, 4.13; 95% confidence interval, 1.27-13.5; P = 0.019). Conclusions The potential therapeutic window of axitinib Cmax in metastatic RCC was estimated at 12.4-40.2ng/mL. Pharmacokinetically guided dose titration using therapeutic drug monitoring may improve the efficacy and safety of axitinib, warranting further investigation in a larger patient population.

Pharmacokinetics of Neoadjuvant Axitinib Influenced the Efficacy in Patients With Advanced Renal Cell Carcinoma.

Although axitinib shows a good objective response rate and acceptable tolerability for advanced renal cell carcinoma, substantial differences in drug concentrations among individuals have hampered the reliable administration of the drug in a neoadjuvant setting. This study aimed to evaluate the relationship between axitinib pharmacokinetics and clinical efficacy in patients with advanced renal cell carcinoma treated in a neoadjuvant setting. We retrospectively reviewed 16 patients who underwent neoadjuvant axitinib treatment from prospective phase 2 study cohorts treated with axitinib and assessed whether the drug concentration was associated with clinical efficacy for primary tumors of advanced metastatic/oligometastatic clear cell renal cell carcinoma. Axitinib was administered orally at a starting dose of 5 mg twice daily for 2 months in principle before the operation, and the axitinib pharmacokinetics were examined. Best response, reduction rate, adverse events (AEs), and surgical complication were assessed. Four patients (25.0%) showed a partial response, and 12 (75.0%) had stable disease, with a mean reduction rate of 22.8%. No progressive disease was noted, and 9 of the 16 patinets (56.3%) showed downstaging. The trough level of axitinib significantly correlated with the objective response rate (P=.0052) and best tumor reduction (P=.0128). All AEs could be safely managed until termination of the dosing period. With respect to perioperative complications, grade 2 anemia was observed. Neoadjuvant axitinib treatment showed acceptable antitumor activity and safety profile for advanced renal cell carcinoma. The pharmacokinetics of neoadjuvant axitinib influenced the efficacy in patients with advanced renal cell carcinoma.

MP16-08 CONTRIBUTION OF GENETIC POLYMORPHISMS RELATED TO AXITINIB PHARMACOKINETICS TO THE CLINICAL SAFETY AND EFFICACY IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2017MP16-08 CONTRIBUTION OF GENETIC POLYMORPHISMS RELATED TO AXITINIB PHARMACOKINETICS TO THE CLINICAL SAFETY AND EFFICACY IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA Ryoma Igarashi, Norihiko Tsuchiya, Takamitsu Inoue, Nobuhiro Fujiyama, Kazuyuki Numakura, Hiroshi Tsuruta, Hideaki Kagaya, Atsushi Maeno, Mitsuru Saito, Shintaro Narita, Takenori Nioka, Masatomo Miura, Shigeru Sato, and Tomonori Habuchi Ryoma IgarashiRyoma Igarashi More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Nobuhiro FujiyamaNobuhiro Fujiyama More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Hideaki KagayaHideaki Kagaya More articles by this author , Atsushi MaenoAtsushi Maeno More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Takenori NiokaTakenori Nioka More articles by this author , Masatomo MiuraMasatomo Miura More articles by this author , Shigeru SatoShigeru Sato More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.514AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Axitinib is approved for use in a second-line therapy for metastatic renal cell carcinoma (mRCC). The predictions of adverse events and efficacy may contribute to the development of personalized medicine. In this study, axitinib pharmacokinetics were analyzed, and the relationships between genetic polymorphisms, the frequency of adverse events, objective responses, and survival were evaluated. METHODS A total of 53 patients with mRCC treated with axitinib were analyzed. High-performance liquid chromatography was used to measure the serum axitinib levels. AUC0–12 (ng·h/mL) was calculated using the serum levels at 0, 2, 4, 8, and 12 h following administration (C0, C2, C4, C8, C12, respectively; ng/mL) on day 7 of the treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RELP. RESULTS The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. The mean C0 and AUC0–12 values in patients with UGT1A1 polymorphism of a poor metabolizer (*6/*6, *6/*28, and *28/*28) were significantly higher than in those with UGT1A1 polymorphism of an extensive metabolizer (*1/*1, *1/*6, *1/*28, *27/*28; p = 0.045 and P =0.035, respectively). The mean AUC0–12 value in patients with SLCO1B1 *15 was significantly higher than that in those without (p = 0.038). The incidence of hand-foot syndrome = G2, hypothyroidism = G2, increased aspartate aminotransferase = G1, and increased alanine aminotransferase = G1 in patients with C0 = 10 ng/mL were significantly higher than that in those with C0 < 10 ng/mL (p = 0.013, P = 0.005, P = 0.037, and P = 0.005). The overall survival in patients with C0 = 5 ng/mL was significantly better than that in those with C0 < 5 ng/mL (p = 0.022). CONCLUSIONS The UGT1A1 and SLCO1B1 were significantly associated with serum axitinib levels. Axitinib trough levels predict therapeutic response in patients with mRCC. The optimal trough level of axitinib may be 5 to 10 ng/mL to achieve an effective treatment without severe adverse events. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e182 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ryoma Igarashi More articles by this author Norihiko Tsuchiya More articles by this author Takamitsu Inoue More articles by this author Nobuhiro Fujiyama More articles by this author Kazuyuki Numakura More articles by this author Hiroshi Tsuruta More articles by this author Hideaki Kagaya More articles by this author Atsushi Maeno More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Takenori Nioka More articles by this author Masatomo Miura More articles by this author Shigeru Sato More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The impact of UGT1A1 and SLCO1B1 genetic polymorphisms and pharmacokinetics of axitinib on clinical safety and efficacy in patients with metastatic renal cell carcinoma.

448 Background: We investigated the impact of genetic polymorphisms and pharmacokinetics of axitinib on adverse events, objective responses, and survival in patients with metastatic renal cell carcinoma (mRCC). Methods: In total, 53 patients with mRCC treated with axitinib were analyzed. Patient was classified as favorable (n = 5), intermediate (n = 36), and poor (n = 12) using the MSKCC risk classification system. High-performance liquid chromatography was used to measure serum axitinib levels. AUC0–12 (ng∙h/mL) was calculated using various serum levels at 0 to 12 h (C0–C12) following administration on day 7 of treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RFLP analysis. Results: The most frequently reported ≥ G3 adverse events were hypertension (43.3%), proteinuria (30.2%), and anorexia (20.1%). The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. Patients with axitinib C0 ≥ 10 ng/mL had a significantly higher rate of hand-foot syndrome ≥ G2 and hypothyroidism ≥ G2 than those with axitinib C0 &lt; 10 ng/mL (p = 0.013, p = 0.005). The overall survival in patients with axitinib C0 ≥ 5 ng/mL was significantly better than that in those with axitinib C0 &lt; 5 ng/mL (p = 0.022). The mean C0 and AUC0–12 values in patients with a poor metabolizer (*6/*6, *6/*28, and *28/*28) of UGT1A1 polymorphism were significantly higher than those in patients with an extensive metabolizer (p = 0.045, p = 0.035, respectively). The mean AUC0–12 value in patients with the SLCO1B1 *15 was significantly higher than that in those without the SLCO1B1 *15 (p = 0.038). Conclusions: Serum axitinib levels were associated with adverse events and overall survival of patients with mRCC. The genetic polymorphisms in UGT1A1 and SLCO1B1 may affect serum axitinib levels in patients with mRCC. Pharmacokinetics and genetic polymorphisms play important roles in the outcomes of patients with mRCC treated with axitinib.

Lack of effect of smoking status on axitinib pharmacokinetics in patients with non-small-cell lung cancer.

Axitinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, is approved for second-line treatment of advanced renal cell carcinoma. Axitinib is partially metabolized by cytochrome P450 1A2, which is induced by chronic heavy smoking. The effect of smoking on axitinib pharmacokinetics was evaluated in a non-small-cell lung cancer (NSCLC) patient population with a large number of active and ex-smokers. Data were pooled from six clinical studies-serial pharmacokinetics from two healthy volunteer studies (n=58) and sparse pharmacokinetics from four NSCLC studies (n=152)-for a nonlinear mixed effects modeling (NONMEM v7.2) analysis. Demographics, smoking status, liver and renal function status, and Eastern Cooperative Oncology Group performance status were tested as covariates. There were 83 (40%) active smokers and 56 (27%) ex-smokers in the pooled dataset. Axitinib pharmacokinetics was adequately described with a linear, two-compartment model with a lagged first-order absorption. Final parameter estimates (inter-individual variability) were 16.1L/h (59.1%) and 45.3L (54.4%) for systemic clearance (CL) and central volume of distribution (Vc), respectively. Smoking status was found not to alter CL or Vc. Asian ethnicity and body weight were significant covariates for Vc, but were not considered clinically relevant since individual values of Vc for Asians were within the range of non-Asians. Based on this analysis, smoking status does not affect area under plasma concentration-time curve, and thus no dose adjustment is required for smokers.

ADVL1315: A phase 1 study of the VEGF receptor tyrosine kinase inhibitor axitinib (INLYTA, IND# 123101) in children with recurrent or refractory solid tumors—A Children's Oncology Group study.

10558Background: Axitinib is a small molecule that inhibits receptor tyrosine kinases VEGFR1-3. A phase I trial evaluating dose limiting toxicities (DLT), the maximally tolerated dose (MTD) and the pharmacokinetics (PK) of axitinib was conducted in children with refractory solid tumors. Methods: Oral axitinib tablets were administered bid, continuously in 28-day cycles. Dose levels 2.4 and 3.2 mg/m2/dose were evaluated using a rolling 6 design. Serial PK were obtained in Cycle 1. Results: As of December 11, 2015, 17 patients were enrolled with 1 ineligible (inadequate time from prior therapy). The median age was 14 yrs (range 5-17 yrs); 9 were male. Patients received a median 3 prior chemotherapy regimens (range 1-8). Cancer diagnoses included soft tissue sarcomas (7), Ewing (2) and osteosarcoma (1), neuroblastoma (2), Wilms tumor (1), hepatoblastoma (1), hepatocellular carcinoma (1), medullary carcinoma (1), and epithelial-myoepithelial carcinoma (1). Toxicity data are available for 15 patients (6 at dos...

Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib.

Axitinib, an inhibitor of vascular endothelial growth factor (VEGF) receptors, is approved as second-line treatment for advanced renal cell carcinoma (RCC). Agents targeting the VEGF pathway may induce renal toxicities, which may be influenced by pre-existing renal dysfunction. The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. Effect of renal function (baseline creatinine clearance [CrCL]) on axitinib clearance was evaluated in a population pharmacokinetic model in 207 patients with advanced solid tumors who received a standard axitinib starting dose, and in 383 healthy volunteers. Axitinib safety according to baseline CrCL was assessed in previously treated patients with RCC (n = 350) who received axitinib in the phase 3 AXIS study. Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6L/h, respectively, in individuals with normal renal function (≥90ml/min; n = 381), mild renal impairment (60-89ml/min; n = 139), moderate renal impairment (30-59ml/min; n = 64), severe renal impairment (15-29ml/min; n = 5), and end-stage renal disease (<15ml/min; n = 1). The population pharmacokinetic model adequately predicted axitinib clearance in individuals with severe renal impairment or end-stage renal disease. Grade ≥3 adverse events (AEs) were reported in 63% of patients with normal renal function or mild impairment, 77% with moderate impairment, and 50% with severe impairment; study discontinuations due to AEs were 10%, 11%, and 0%, respectively. Axitinib pharmacokinetics and safety were similar regardless of baseline renal function; no starting-dose adjustment is needed for patients with pre-existing mild to severe renal impairment.

Abstract CT120: Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer

Abstract Introduction: Hepatobiliary excretion is the major elimination pathway for axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, approved for second-line treatment of advanced renal cell carcinoma. A formal hepatic impairment (HI) study was previously conducted in subjects with Child-Pugh A (CPA) and Child-Pugh B (CPB) disease but who were otherwise healthy to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of axitinib following a single 5 mg oral dose. The safety and PK of axitinib were further evaluated in CPA and CPB patients (pts) with advanced hepatocellular carcinoma (HCC) following continuous multiple axitinib dosing. Methods: Two study portions (randomized double-blind portion of axitinib versus placebo, and non-randomized portion) were conducted in parallel in pts with advanced HCC after failure of one prior antiangiogenic therapy. In the non-randomized portion, the effect of HI on safety and PK were evaluated in HCC CPA (starting dose: 5 mg twice a day [BID]) and CPB (Score 7, starting dose: 2 mg BID) pts. This was also intended to identify the recommended starting dose of axitinib in HCC CPB pts. Serial PK samples up to 8 hour postdose were collected at steady state (Cycle 1 Day 15). Results: Data from 15 CPA and 7 CPB pts were available for safety analysis. Most pts were male (n = 17) and Asian (n = 21). Overall, the most frequently reported all-causality treatment emergent adverse events (TEAE) in all, CPA and CPB pts were fatigue (63.6%, 80% and 28.6%), decreased appetite (54.5%, 46.7% and 71.4%), diarrhea (45.5%, 60% and 14.3%), hypertension (45.5%, 46.7% and 42.9%), and palmar-plantar erythrodysesthesia syndrome (45.5%, 53.3% and 28.6%). Overall, the most frequently reported Grade ≥3 TEAEs in all, CPA and CPB pts were hypertension (27.3%, 26.7% and 28.6%), fatigue (18.2%, 20% and 14.3%) and hyponatraemia (18.2%, 6.7% and 42.9%). One out of 6 evaluable CPB pts treated with 2 mg BID experienced Cycle 1 dose limiting toxicity (proteinuria; &amp;gt;3.5 g/24 hours). PK samples were collected from 12 CPA and 7 CPB pts (AUC0-24 and CL/F reported for 8 CPA and 6 CPB pts, respectively). In CPA and CPB pts, the geometric mean (geometric% coefficient of variance [CV]) values for axitinib AUC0-24 were 311 (63) and 316 (118) ng.hr/mL, respectively. The geometric mean (geometric% CV) values for axitinib CL/F were 32.2 (63) and 12.7 (118) L/hour, respectively, indicating that axitinib CL/F is decreased with increasing HI. Conclusions: The safety profile of axitinib in HCC CPA and CPB pts in this study was consistent with the known safety profile of axitinib. Axitinib plasma exposures were comparable in CPB pts receiving 2 mg BID axitinib and CPA pts receiving 5 mg BID axitinib. These data are in agreement with the previous single-dose HI study and further support that 2 mg BID is an appropriate axitinib starting dose for CPB pts with HCC. Citation Format: Yoon-Koo Kang, Tara E. Seery, Mina Kato, Debasis Chakrabarti, Olga Valota, Ying Chen, Jie Tang, Yazdi K. Pithavala, Masatoshi Kudo. Axitinib safety and pharmacokinetics in Child-Pugh A and Child-Pugh B patients with advanced hepatocellular cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT120. doi:10.1158/1538-7445.AM2015-CT120

8 Association of pharmacokinetics of axitinib with treatment outcome and adverse events in advanced renal cell carcinoma patients

8 Association of pharmacokinetics of axitinib with treatment outcome and adverse events in advanced renal cell carcinoma patients

Association of pharmacokinetics of axitinib with treatment outcome and adverse events in advanced renal cell carcinoma patients.

506 Background: Therapeutic drug monitoring (TDM) has been recognized as a useful tool for optimizing the dose of many drugs. The effectiveness of TDM for molecular targeted agents, however, has not so far been established. In this study, we examined the associations between pharmacokinetics of axitinib (AXI) and adverse events (AEs) and clinical outcomes in patients with advanced renal cell carcinoma (aRCC). Methods: The pharmacokinetics of AXI was examined in 24 patients (18 males and 6 females) with aRCC. The plasma AXI levels were measured using high-performance liquid chromatography and a pharmacokinetic study was performed on day 7 in the first cycle. Subsequently, the associations between the pharmacokinetics of AXI and the occurrence and grade of AEs, best tumor response, and progression-free survival (PFS) were investigated. Results: All the patients were been treated with 10 mg/day of AXI at the day of pharmacokinetics and the trough levels were ranged between 1.2 and 70.97 ng/mL. The trough levels were significantly associated with the occurrence of hypertension, hyperthyroidism, and grade 1 or higher proteinuria (p=0.037, 0.024, 0.027 by Mann-Whitney test, respectively), and were associated with the best tumor response (by Mann-Whitney test, p=0.043) (Table 1). Patients with 5.0 ng/mL of higher trough levels of AXI showed a tendency toward longer PFS than those with the trough levels less than 5.0 ng/mL (Table 2). Conclusions: TDM of AXI in patients with aRCC may be useful to determine the adequate dose and prevent severe AEs. Further studies are mandatory to conclude the usefulness of TDM of AXI for the long-term clinical efficacy in patients with aRCC. [Table: see text] [Table: see text]

Pharmacokinetics of single-agent axitinib across multiple solid tumor types.

Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors, showed antitumor activity as a single agent against several solid tumor types in Phase II and III trials. This study was conducted to evaluate axitinib pharmacokinetics across a variety of solid tumors. The current study analyzed the pharmacokinetics of axitinib in 110 patients with non-small cell lung cancer (NSCLC), thyroid cancer, or melanoma from three Phase II trials plus 127 healthy volunteers, using nonlinear mixed-effects modeling. Boxplots of maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of data from these tumor populations was compared to C max and AUC from the final population pharmacokinetic model developed for metastatic renal cell carcinoma (mRCC) to compare axitinib pharmacokinetics across different tumor types. Axitinib disposition based on data from 237 subjects was best described using a two-compartment model with first-order absorption and lag time. Population estimates for systemic clearance, central volume of distribution, absorption rate constant, absolute bioavailability, and lag time were 20.1L/h, 56.2L, 1.26/h(-1), 0.663, and 0.448h, respectively. Statistically significant covariates included gender on clearance, and body weight on central volume of distribution. However, predicted changes due to gender and body weight were found not clinically meaningful. The final analysis indicated that the pharmacokinetic model for mRCC was able to successfully describe axitinib pharmacokinetics in patients with NSCLC, thyroid cancer, and melanoma. The pharmacokinetics of axitinib appears to be similar across a variety of tumor types.

Population pharmacokinetic analysis of axitinib in healthy volunteers

Axitinib 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. Plasma 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). A 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 . The 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.

Pharmacodynamic study using FLT PET/CT in patients treated with axitinib.

2537 Background: Axitinib (AX) is a potent VEGFR2 TKI. The objective of this study was to characterize tumor vascular and proliferative changes in patients treated with AX. Methods: Thirty pts with solid malignancies with at least one target lesion appropriate for FLT PET/CT imaging were enrolled. Pts were treated in Cycle #1 (C1) with AX at 5 mg BID x 2 wks, followed by a 1 wk drug holiday. Subsequent cycles continued the AX BID on a continuous basis until progression or unacceptable toxicity. In cohort A, FLT PET/CT was obtained at baseline, C1D14 (during AX) and C1D21 (AX withdrawal). Cohort B used the same treatment schedule, but FLT PET/CT was obtained on C1D14, C1D16 and C1D21. At each imaging time, peak FLT Standardized Uptake Values (SUVpeak), AX pharmacokinetics and plasma VEGF levels were obtained. Results: Of the 30 total pts, 28 had at least 1 PET/CT scan with 24 completing all planned PET/CT scans (13 in Cohort A; 11 in Cohort B). Strong proliferative flare (36% increase in SUVpeak from C1D14 to C1D21) was observed in majority of pts with most of the flare occurred within two days after AX withdrawal (25% increase in SUVpeak from C1D14 by C1D16). A robust vascular flare paralleled proliferative flare (R=0.57). A trend linking short progression free survival with high withdrawal flare was seen (44% increase in SUVpeak for PFS ≤ 6mo vs 11% increase in SUVpeak for PFS &gt; 6 mo; p=0.14). VEGF levels and AX PK levels increased during treatment, followed by decrease during withdrawal. Conclusions: The observed AX pharmacodynamics is consistent with our prior observation with another VEGFR TKI and suggests that acute AX withdrawal results in a robust withdrawal flare. This information suggests that the timing of cytotoxic chemotherapy during the flare may increase the therapeutic index, as opposed to concurrent administration which may be antagonistic. This study also shows the power of quantitative molecular imaging, which can simultaneous evaluate treatment response heterogeneity, as well as compensatory effects that may lead to early treatment failure. Clinical trial information: NCT00859118.

Clinical Pharmacology of Axitinib

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 5mg twice daily, taken with or without food. Dose increase (up to a maximum of 10mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1h), 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 4h 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 0-24h (AUC24) were 27.8ng/mL (79%) and 265ng·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 clearance of axitinib were identified.

Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours

Background:Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy.Methods:A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m–2 weekly), docetaxel (100 mg m–2 every 3 weeks) or capecitabine (1000 or 1250 mg m–2 b.i.d., days 1–14).Results:Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand–foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents.Conclusions:Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

Background:This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.Methods:In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.Results:Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.Conclusion:Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.

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

To evaluate the effect of food on axitinib pharmacokinetics in healthy volunteers with two different crystal polymorphs. Two separate open-label, randomized, single-dose, three-period, crossover trials were conducted. Study I, conducted first using 5-mg axitinib Form IV film-coated immediate-release (FCIR) tablets, enrolled 18 subjects to compare fed versus fasted states and 24 subjects to evaluate the effect of timing of food consumption on axitinib pharmacokinetics. Study II enrolled 30 subjects to assess the effect of food using 5-mg axitinib Form XLI FCIR tablets. Subjects received axitinib after overnight fasting, with limited fasting or, depending on the study design, after consuming high-fat, high-calorie or moderate-fat, standard-calorie meals. For Form IV FCIR, compared with overnight fasting, axitinib plasma exposure [area under the concentration curve (AUC)] was decreased 23 % when administered with food. For Form XLI FCIR, mean axitinib plasma AUC and maximum plasma concentration (C(max)) were 19 and 11 % higher, respectively, with a high-fat, high-calorie meal compared with overnight fasting. When Form XLI FCIR was administered with moderate-fat, standard-calorie meal, AUC and C(max) were 10 and 16 % lower compared with overnight fasting. Both formulations were well tolerated. Adverse events, mostly gastrointestinal (7 % with Form IV FCIR and 13 % with Form XLI FCIR), were mild to moderate in both studies. 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.

A Phase I study to evaluate the pharmacokinetics of axitinib (AG-13736) in healthy Chinese volunteers

To assess axitinib plasma pharmacokinetics and safety of single oral doses of axitinib under fed conditions in healthy Chinese volunteers. This Phase I, open-label study evaluated single dosing of axitinib in 14 healthy Chinese volunteers. Axitinib was administered as 5-, 7-, and 10-mg doses under fed conditions in study periods 1, 2, and 3, respectively, followed by pharmacokinetic assessments and safety monitoring. A washout period ≥ 7 days was provided between successive axitinib doses. Blood samples were collected during each period up to 32 h post-dose for pharmacokinetic analysis. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods. Estimates (geometric mean) of axitinib AUC(inf) were 150, 251, and 321 ng × h/ml for doses of 5, 7, and 10 mg, respectively, reflecting a dose-proportional increase in AUC(inf) (increments of 1 : 1.7 : 2.1 for dose increments of 1 : 1.4 : 2, respectively). Geometric mean estimates of maximum observed plasma concentration (Cmax) were 33.5, 51.1, and 69.4 ng/ml, respectively, which also showed dose proportionality. Axitinib plasma pharmacokinetics was similar to those previously observed in healthy Caucasians, with geometric mean values (% geometric coefficient of variation) for axitinib plasma AUC(inf) 150 ng × h/ml (62%) versus 125 ng × h/ml (60%), respectively. Axitinib was well tolerated, with no serious adverse events or discontinuations; one adverse event of mild abdominal distension was observed. In healthy Chinese subjects, single dosing of axitinib demonstrated dose-proportional pharmacokinetics. Axitinib pharmacokinetics in this population was similar to those previously observed in healthy Caucasians, suggesting a lack of ethnic differences.

Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer

Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m(2)), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Axitinib (5 mg BID) and gemcitabine (1,000 mg/m(2)) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.

Axitinib for the Management of Metastatic Renal Cell Carcinoma

In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2–6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advancedRCCpreviously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable noncumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95%CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95%CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6).In the three studies, themost common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients.An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.