Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma
- 575 Downloads
Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.
Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.
Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group.
Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.
KeywordsPharmacodynamics Pharmacokinetics Bortezomib Multiple myeloma Proteasome inhibition
The authors would like to acknowledge editorial assistance from Steve Hill and Jane Saunders of FireKite during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc. Research was supported in part by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Conflict of interest statement
DER: consultancy/advisory role for, and research funding from, Millennium Pharmaceuticals and Johnson & Johnson. SL: consultancy/advisory role for Amgen, BMS, Millennium Pharmaceuticals, Ortho-Biotech, Novartis. AFM: Honoraria from Millennium Pharmaceuticals speakers bureau. KV: renumeration from Millennium Pharmaceuticals. RN: renumeration from Millennium Pharmaceuticals. WJR: renumeration from Millennium Pharmaceuticals. MK: renumeration from, and stock ownership of, Millennium Pharmaceuticals. LLVL: renumeration from Millennium Pharmaceuticals. PZ: renumeration from, and stock ownership of, Johnson & Johnson. AKS: consultancy/advisory role for, and research funding from, Millennium Pharmaceuticals. DS, GC, CS, HB, and MA have no disclosures.
- 1.Millennium Pharmaceuticals Inc. (2008) VELCADE® (bortezomib) for Injection. Prescribing information. Cambridge, MA, USA; Issued June 2008, Rev 9Google Scholar
- 2.Janssen-Cilag International NV (2009) VELCADE® (bortezomib). Summary of product characteristics, Beerse, BelgiumGoogle Scholar
- 6.Cavo M, Tacchetti P, Patriarca F et al (2008) Superior complete response rate and progression-free survival after autologous transplantation with up-front Velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood 112:65aGoogle Scholar
- 16.San Miguel JF, Schlag R, Khuageva NK et al (2008) Updated follow-up and results of subsequent therapy in the phase III VISTA trial: bortezomib plus melphalan-prednisone versus melphalan-prednisone in newly diagnosed multiple myeloma. Blood 112:242aGoogle Scholar
- 23.Bladé J, Samson D, Reece D et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma subcommittee of the EBMT. European group for blood and marrow transplant. Br J Haematol 102:1115–1123CrossRefPubMedGoogle Scholar