Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma |
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Authors: | Donna E. Reece Dan Sullivan Sagar Lonial Ann F. Mohrbacher Gurkamal Chatta Chaim Shustik Howard Burris III Karthik Venkatakrishnan Rachel Neuwirth William J. Riordan Michael Karol Lisa L. von Moltke Milin Acharya Peter Zannikos A. Keith Stewart |
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Affiliation: | 1. Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada 2. H. Lee Moffitt Cancer Center, Tampa, FL, USA 3. Emory University Hospital, Atlanta, GA, USA 4. University of Southern California, Los Angeles, CA, USA 5. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 6. Royal Victoria Hospital, Montreal, QC, Canada 7. The Sarah Cannon Cancer Center, Nashville, TN, USA 8. Millennium Pharmaceuticals Inc, Cambridge, MA, USA 11. Synta Pharmaceuticals Corp, Lexington, MA, USA 9. Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Raritan, NJ, USA 10. Mayo Clinic, Scottsdale, AZ, USA
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Abstract: | Purpose Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. Methods 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. Results Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102?C112?L/h for first dose; 15?C32?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. Conclusions 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. |
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