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

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 dose-normalized 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).

Conflict of interest statement

Conflict of interest statement:

PML is a consultant for Millennium Pharmaceuticals, Inc.

KV, RN and D-LE are employees of Millennium Pharmaceuticals, Inc.

MAR is a consultant for Concordia Pharmaceuticals/Averion International Corp.

CHT is an employee of Johnson & Johnson, Ortho Biotech Oncology R&D.

All other authors have no conflicts of interest to declare.

Figures

Figure 1

Mean dose-normalized plasma concentration–time profiles of bortezomib on days (A) 1 and (B) 8 of cycle 1 by hepatic function group.

Figure 1

Mean dose-normalized plasma concentration–time profiles of bortezomib on days (A) 1 and (B) 8 of cycle 1 by hepatic function group.

Figure 2

Individual (filled circles) and geometric mean (open squares) values of dose-normalized AUC0-tlast on day 1 (A) and day 8 (B), and dose-normalized Cmax on day 1 (C) and day 8 (D), by hepatic function group.