Carfilzomib plasma concentration-time profile following a 30-minute IV infusion of carfilzomib, and proteasome activity and active-site binding probe subunit occupancy in PBMCs. (A) Mean (standard deviation) carfilzomib plasma concentration time profile after administration via a 30-minute IV infusion of 20, 70, or 88 mg/m2 carfilzomib. (B) Dose-dependent proteasome activity and active-site binding probe subunit occupancy in PBMCs at 1 hour post-dose on C2D1 (unless otherwise noted) in CHAMPION-1 and PX-171-007; 20 mg/m2 (C1D1), n = 10-11; 20 mg/m2, n = 3; 27 mg/m2, n = 3; 36 mg/m2, n = 20-24; 45 mg/m2, n = 3-8; 56 mg/m2, n = 5-13; and 70 mg/m2, n = 7. Data for 20, 27, 36, 45, and 56 mg/m2 doses are from the PX-171-007 study (twice-weekly dosing)7 ; 20 mg/m2 (C1D1 only) and 70 mg/m2 data are from the CHAMPION-1 study (once-weekly dosing). Values (relative to C1D1 pre-dose) are presented as mean (± standard error of the mean). CT-L activity was measured by the fluorescent enzymatic cleavage LLVY-AMC assay,14,15 whereas subunit occupancy was measured by the ProCISE assay.16 The ProCISE assay employs a proteasome active-site binding probe that generates a signal from catalytic sites that are not already bound by inhibitor (ie, carfilzomib); subunit (probe) occupancy is thus proportional to the presence of active subunit. (C) Time-course of inhibition, and recovery of proteasome activity and active-site binding probe subunit occupancy in peripheral blood at 1 hour post-dose on C2D1; 20 mg/m2, n = 3-48; 36 mg/m2, n = 4-24; and 70 mg/m2; n = 7-11. LMP2, low molecular mass polypeptide 2; LMP7, low molecular mass polypeptide 7; MECL-1, multi-catalytic endopeptidase complex-like 1.
