Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma

Abstract

This phase I study compared pharmacokinetics and pharmacodynamics, and assessed safety and efficacy of intravenous and subcutaneous administration of bortezomib. Relapsed or refractory multiple myeloma patients were randomized to receive bortezomib by standard intravenous bolus (n=12) or subcutaneous injection (n=12) at the recommended dose and schedule (1.3 mg/m 2 , days 1, 4, 8, 11; eight 21-day cycles). Plasma bortezomib concentration and percent 20S proteasome inhibition were measured at multiple time points on days 1 and 11, cycle 1. Systemic bortezomib exposure was similar between arms. As expected, mean maximum plasma concentration was lower and took longer to reach following subcutaneous administration. Overall 20S proteasome inhibition was similar between arms. Safety profile and response rate for the subcutaneous arm did not appear inferior to the intravenous arm, with good local tolerance of subcutaneous injection. Based on these exploratory findings, subcutaneous administration offers an alternative option to intravenous injection (ClinicalTrials.gov identifier: NCT00291538).

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

“…Inhibition levels were also equivalent in patients with MM receiving 20 mg/m 2 carfilzomib as a 2‐ to 10‐min or 30‐min infusion, which is consistent with results reported in animals (Yang et al , 2011). It is noteworthy that the overall level of CT‐L inhibition seen with carfilzomib is higher than the 65–70% inhibition rate reported in bortezomib‐treated patients (Orlowski et al , 2002; Papandreou et al , 2004; Moreau et al , 2008). Using ProCISE, we also demonstrated that the administration of carfilzomib inhibits proteasome subunit occupancy in bone marrow–derived tumour cells.…”

Treatment of relapsed and refractory multiple myeloma

“…Trials and retrospective analyses have shown that retreatment with bortezomib is feasible and effective and does not incur cumulative toxicity. [50][51][52] Lenalidomide retreatment is also feasible and may induce responses in up to 44 % of relapsed patients, and is better than retreatment with thalidomide. 51,53 Tolerability is another important consideration, and factors like neuropathy, myelosuppression and thrombosis may influence the choice of therapy.…”

Nonproteasomal Targets of the Proteasome Inhibitors Bortezomib and Carfilzomib: a Link to Clinical Adverse Events

“…Subsequently, we incubated whole blood for 1 hour with 100 nmol/L of bortezomib, a concentration/ exposure period maintained in patients receiving a dose of 1.3 mg/m 2 (19,27,28), and observed potent inhibition of CatG by ABP detection in isolated PBMCs. Carfilzomib, on the other hand, did not affect CatG activity despite equivalent levels of proteasome inhibition to bortezomib (Fig.…”