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

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma,10.1007/s00280-010-1283-3,Cancer Chemo

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma   (Citations: 3)
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Donna E. Reece, Dan Sullivan, Sagar Lonial, Ann F. Mohrbacher, Gurkamal Chatta, Chaim Shustik, Howard Burris, Karthik Venkatakrishnan, Rachel Neuwirth, William J. Riordan, Michael Karol, Lisa L. von Moltkehttp://academic.research.microsoft.com/io.ashx?type=5&id=32518004&selfId1=0&selfId2=0&maxNumber=12&query=
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.
Journal: Cancer Chemotherapy and Pharmacology - CANCER CHEMOTHER PHARMACOL , vol. 67, no. 1, pp. 57-67, 2011
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    • ...The IC50 concentrations determined in the caspase assays for the MM cell line U266 and the non-Hodgkin lymphoma cell line DOHH-2 after incubation with bortezomib (12.0 and 11.4 nM after 24 h; 2.1 and 4.4 nM after 48 h) are in the range of those previously reported and within clinically achievable plasma bortezomib concentrations of around 55–120 ng/mL (143–313 nM) [23, 24]...

    Martin Schmidt-Hieberet al. In vitro cytotoxicity of the novel antimyeloma agents perifosine, bort...

    • ...Pharmacokinetic studies in human plasma indicate that bortezomib displays a rapid initial distribution phase [10–12], with plasma concentrations dropping more than 10-fold within an hour post-dose [12]...

    Bret Bannermanet al. Preclinical evaluation of the antitumor activity of bortezomib in comb...

    • ...[36]. However, it should be noted that the Cmax is achieved only directly after infusion and neglible compound amounts are measured after 60 min, whereas at concentrations >5 ng/mL proteasome inhibition appears to reach a plateau of approximately 70% to 80% [36, 37]...
    • ...[36]. However, it should be noted that the Cmax is achieved only directly after infusion and neglible compound amounts are measured after 60 min, whereas at concentrations >5 ng/mL proteasome inhibition appears to reach a plateau of approximately 70% to 80% [36, 37]...

    Martin Schmidt-Hieberet al. In vitro effects of perifosine, bortezomib and lenalidomide against he...

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