Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction

Phase I NCI Organ Dysfunction Working Group Study NCI-6432

Patricia M. LoRusso, Karthik Venkatakrishnan, Ramesk K Ramanathan, John Sarantopoulos, Daniel Mulkerin, Stephen I. Shibata, Anne Hamilton, Afshin Dowlati, Sridhar Mani, Michelle A. Rudek, Chris H. Takimoto, Rachel Neuwirth, Dixie Lee Esseltine, Percy Ivy

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Purpose: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Experimental Design: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m 2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m 2, respectively, up to a 1.3 mg/m 2 maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dosenormalized bortezomib exposure (AUC 0-tlast) or C max compared with patients with normal function. Mean dose-normalized AUC 0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m 2.

Original languageEnglish (US)
Pages (from-to)2954-2963
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number10
DOIs
StatePublished - May 15 2012
Externally publishedYes

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Liver Diseases
Pharmacokinetics
Safety
Liver
Neoplasms
Area Under Curve
Proteasome Inhibitors
National Cancer Institute (U.S.)
Bortezomib
Patient Safety
Research Design
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction : Phase I NCI Organ Dysfunction Working Group Study NCI-6432. / LoRusso, Patricia M.; Venkatakrishnan, Karthik; Ramanathan, Ramesk K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I.; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A.; Takimoto, Chris H.; Neuwirth, Rachel; Esseltine, Dixie Lee; Ivy, Percy.

In: Clinical Cancer Research, Vol. 18, No. 10, 15.05.2012, p. 2954-2963.

Research output: Contribution to journalArticle

LoRusso, PM, Venkatakrishnan, K, Ramanathan, RK, Sarantopoulos, J, Mulkerin, D, Shibata, SI, Hamilton, A, Dowlati, A, Mani, S, Rudek, MA, Takimoto, CH, Neuwirth, R, Esseltine, DL & Ivy, P 2012, 'Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: Phase I NCI Organ Dysfunction Working Group Study NCI-6432', Clinical Cancer Research, vol. 18, no. 10, pp. 2954-2963. https://doi.org/10.1158/1078-0432.CCR-11-2873
LoRusso, Patricia M. ; Venkatakrishnan, Karthik ; Ramanathan, Ramesk K ; Sarantopoulos, John ; Mulkerin, Daniel ; Shibata, Stephen I. ; Hamilton, Anne ; Dowlati, Afshin ; Mani, Sridhar ; Rudek, Michelle A. ; Takimoto, Chris H. ; Neuwirth, Rachel ; Esseltine, Dixie Lee ; Ivy, Percy. / Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction : Phase I NCI Organ Dysfunction Working Group Study NCI-6432. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 10. pp. 2954-2963.
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abstract = "Purpose: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Experimental Design: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m 2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m 2, respectively, up to a 1.3 mg/m 2 maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dosenormalized bortezomib exposure (AUC 0-tlast) or C max compared with patients with normal function. Mean dose-normalized AUC 0-tlast was increased by approximately 60{\%} on day 8 in patients with moderate or severe impairment. Conclusions: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m 2.",
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T1 - Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction

T2 - Phase I NCI Organ Dysfunction Working Group Study NCI-6432

AU - LoRusso, Patricia M.

AU - Venkatakrishnan, Karthik

AU - Ramanathan, Ramesk K

AU - Sarantopoulos, John

AU - Mulkerin, Daniel

AU - Shibata, Stephen I.

AU - Hamilton, Anne

AU - Dowlati, Afshin

AU - Mani, Sridhar

AU - Rudek, Michelle A.

AU - Takimoto, Chris H.

AU - Neuwirth, Rachel

AU - Esseltine, Dixie Lee

AU - Ivy, Percy

PY - 2012/5/15

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N2 - Purpose: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Experimental Design: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m 2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m 2, respectively, up to a 1.3 mg/m 2 maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dosenormalized bortezomib exposure (AUC 0-tlast) or C max compared with patients with normal function. Mean dose-normalized AUC 0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m 2.

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