Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration–Time Curve for Metastatic Renal-Cell Carcinoma

Yuji Miura, Chiyo Imamura, Keita Uchino, Takeshi Kishida, Nobuaki Matsubara, Toshiaki Shinojima, Keiichi Kondo, Fumiya Hongo, Kenichi Yoshimura, Yusuke Tanigawara, Toshimi Takano

Research output: Contribution to journalArticle

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Abstract

Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand–foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. Conclusion: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity. Individualized dosing of axitinib based on drug exposure remains unknown. In this study we evaluated the efficacy and safety of the recommended axitinib dose on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours in metastatic renal-cell carcinoma. Adjusting to the recommended dose lead to promising efficacy and manageable toxicity. The current study provides novel information to develop individualized axitinib treatment.

Original languageEnglish
JournalClinical Genitourinary Cancer
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Renal Cell Carcinoma
Area Under Curve
Disease-Free Survival
Survival Rate
Confidence Intervals
Hypertension
axitinib
Appetite
Clinical Protocols
Antihypertensive Agents
Fatigue
Blood Pressure
Safety
Pharmaceutical Preparations

Keywords

  • First-dose AUC
  • Kidney cancer
  • mRCC
  • Recommended dose
  • VEGFR inhibitor

ASJC Scopus subject areas

  • Oncology
  • Urology

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Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration–Time Curve for Metastatic Renal-Cell Carcinoma. / Miura, Yuji; Imamura, Chiyo; Uchino, Keita; Kishida, Takeshi; Matsubara, Nobuaki; Shinojima, Toshiaki; Kondo, Keiichi; Hongo, Fumiya; Yoshimura, Kenichi; Tanigawara, Yusuke; Takano, Toshimi.

In: Clinical Genitourinary Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Miura, Yuji ; Imamura, Chiyo ; Uchino, Keita ; Kishida, Takeshi ; Matsubara, Nobuaki ; Shinojima, Toshiaki ; Kondo, Keiichi ; Hongo, Fumiya ; Yoshimura, Kenichi ; Tanigawara, Yusuke ; Takano, Toshimi. / Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration–Time Curve for Metastatic Renal-Cell Carcinoma. In: Clinical Genitourinary Cancer. 2018.
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abstract = "Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6{\%} (95{\%} confidence interval, 65.5-94.1) and 82.6{\%} (95{\%} confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand–foot syndrome, fatigue, and decreased appetite. Eighteen patients (75{\%}) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. Conclusion: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity. Individualized dosing of axitinib based on drug exposure remains unknown. In this study we evaluated the efficacy and safety of the recommended axitinib dose on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours in metastatic renal-cell carcinoma. Adjusting to the recommended dose lead to promising efficacy and manageable toxicity. The current study provides novel information to develop individualized axitinib treatment.",
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author = "Yuji Miura and Chiyo Imamura and Keita Uchino and Takeshi Kishida and Nobuaki Matsubara and Toshiaki Shinojima and Keiichi Kondo and Fumiya Hongo and Kenichi Yoshimura and Yusuke Tanigawara and Toshimi Takano",
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T1 - Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration–Time Curve for Metastatic Renal-Cell Carcinoma

AU - Miura, Yuji

AU - Imamura, Chiyo

AU - Uchino, Keita

AU - Kishida, Takeshi

AU - Matsubara, Nobuaki

AU - Shinojima, Toshiaki

AU - Kondo, Keiichi

AU - Hongo, Fumiya

AU - Yoshimura, Kenichi

AU - Tanigawara, Yusuke

AU - Takano, Toshimi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand–foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. Conclusion: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity. Individualized dosing of axitinib based on drug exposure remains unknown. In this study we evaluated the efficacy and safety of the recommended axitinib dose on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours in metastatic renal-cell carcinoma. Adjusting to the recommended dose lead to promising efficacy and manageable toxicity. The current study provides novel information to develop individualized axitinib treatment.

AB - Background: Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal-cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours (AUC0-12) for sunitinib-pretreated metastatic renal-cell carcinoma patients. Patients and Methods: In this prospective single-arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0-12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0-12 at steady state according to first-dose AUC0-12. The primary end point was the 6-month progression-free survival rate. Results: Twenty-six Japanese patients were enrolled. The median recommended dose based on the first-dose AUC0-12 was 2.5 mg (range, 1-16 mg) twice daily. The 6-month progression-free survival rate for all enrolled patients and per-protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5-94.1) and 82.6% (95% confidence interval, 61.8-93.3), respectively. The most common nonhematologic adverse events were hypertension, hand–foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. Conclusion: Individualized dosing of axitinib based on the first-dose AUC0-12 might have promising efficacy and manageable toxicity. Individualized dosing of axitinib based on drug exposure remains unknown. In this study we evaluated the efficacy and safety of the recommended axitinib dose on the basis of the first-dose area under the concentration–time curve from 0 to 12 hours in metastatic renal-cell carcinoma. Adjusting to the recommended dose lead to promising efficacy and manageable toxicity. The current study provides novel information to develop individualized axitinib treatment.

KW - First-dose AUC

KW - Kidney cancer

KW - mRCC

KW - Recommended dose

KW - VEGFR inhibitor

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