Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

• Published in: Cancer chemotherapy and pharmacology 2011-01, Vol.67 (1), p.57-67
• Main Authors: Reece, Donna E, Sullivan, Dan, Lonial, Sagar, Mohrbacher, Ann F, Chatta, Gurkamal, Shustik, Chaim, Burris, Howard III, Venkatakrishnan, Karthik, Neuwirth, Rachel, Riordan, William J, Karol, Michael, von Moltke, Lisa L, Acharya, Milin, Zannikos, Peter, Keith Stewart, A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacokinetics; Bortezomib; Cancer Research; Dose-Response Relationship, Drug; Female; Half-Life; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple Myeloma - drug therapy; myeloma; Oncology; Original Article; pharmacokinetics; pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prospective Studies; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - pharmacokinetics; Proteasome inhibition; Proteasome Inhibitors; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacokinetics; Recurrence; Treatment Outcome
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-010-1283-3

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 (102-112 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. 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.