Pharmacodynamics of bortezomib and PegLD. (A) Inhibition of the chymotryptic activity of the 20S-proteasome by bortezomib is shown as a function of the administered dose level (in mg/m2). The mean percentage inhibition 1 hour after each dose compared with the pretreatment baseline is shown, along with the standard deviation (SD), for days 1 (□) and 4 (▤). Data were available from only 1 patient at the 0.90 mg/m2 dose level due to an error in processing the other 5 patient's samples. (B) The 20S-proteasome inhibition (± SD) induced by bortezomib alone on days 1 and 4 is compared with mean inhibition on days 8 and 11, when both bortezomib and PegLD are present. The mean percentage inhibition 1 hour after each dose on days 1 and 4 for all patients at each dose level (•, 0.90 mg/m2; ○, 1.05 mg/m2; ▪, 1.20 mg/m2; □, 1.30 mg/m2; ♦, 1.40 mg/m2; ⋄, 1.50 mg/m2) is compared with the mean percentage inhibition on days 8 and 11. (C) Specific activity (mean ± SD) of the chymotrypsin-like proteasome protease is shown at baseline on day 1 and then 1 hour after bortezomib for each of the 6 dose levels of this proteasome inhibitor studied (symbols indicate same dose levels as in panel B). The units for specific activity are picomoles of fluorescent chromophore released per second per milligram of total protein. (D) Proteasome activity is shown at baseline and 1 hour after dosing with either bortezomib alone (mean specific activity ± SD on days 1 and 4, •) or bortezomib in the presence of PegLD (mean specific activity ± SD on days 8 and 11, ○).
