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


ABSTRACT: 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/m(2), 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/m(2) 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/m(2) doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

SUBMITTER: Reece DE 

PROVIDER: S-EPMC3951913 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Reece Donna E DE   Sullivan Dan D   Lonial Sagar S   Mohrbacher Ann F AF   Chatta Gurkamal G   Shustik Chaim C   Burris Howard H   Venkatakrishnan Karthik K   Neuwirth Rachel R   Riordan William J WJ   Karol Michael M   von Moltke Lisa L LL   Acharya Milin M   Zannikos Peter P   Keith Stewart A A  

Cancer chemotherapy and pharmacology 20100320 1


<h4>Purpose</h4>Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.<h4>Methods</h4>Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m(2), 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  ...[more]

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