Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma.

BACKGROUND AND OBJECTIVES: The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m(2) on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY-3021 study and the phase I CAN-1004 study of subcutaneous versus intravenous bortezomib in patients aged ≥18 (MMY-3021) or ≤75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1-3 (MMY-3021) or ≥1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. RESULTS: Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration-time curve from time zero to the last quantifiable timepoint (AUC(last)): 155 vs. 151 ng·h/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN-1004 (mean AUC(last): 195 vs. 241 ng·h/mL); maximum (peak) plasma drug concentration (C(max)) was lower with subcutaneous administration in both MMY-3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to C(max) (t(max)) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (E(max)) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004, and mean area under the effect-time curve from time zero to 72 h was 1,714 versus 1,383 %·h in MMY-3021 and 1,619 versus 1,283 %·h in CAN-1004. Time to E(max) was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. CONCLUSION: Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established.