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

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 Moltke, Milin Acharya, Peter Zannikos, Alexander Keith Stewart

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 (102-112 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.

Original languageEnglish (US)
Pages (from-to)57-67
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Pharmacodynamics
Pharmacokinetics
Multiple Myeloma
Blood
Proteasome Endopeptidase Complex
Plasmas
Safety
Intravenous Administration
Half-Life
Toxicity
Bortezomib
Recovery

Keywords

  • Bortezomib
  • Multiple myeloma
  • Pharmacodynamics
  • Pharmacokinetics
  • Proteasome inhibition

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. / Reece, Donna E.; Sullivan, Dan; Lonial, Sagar; Mohrbacher, Ann F.; Chatta, Gurkamal; Shustik, Chaim; Burris, Howard; Venkatakrishnan, Karthik; Neuwirth, Rachel; Riordan, William J.; Karol, Michael; Von Moltke, Lisa L.; Acharya, Milin; Zannikos, Peter; Stewart, Alexander Keith.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 1, 01.2011, p. 57-67.

Research output: Contribution to journalArticle

Reece, DE, Sullivan, D, Lonial, S, Mohrbacher, AF, Chatta, G, Shustik, C, Burris, H, Venkatakrishnan, K, Neuwirth, R, Riordan, WJ, Karol, M, Von Moltke, LL, Acharya, M, Zannikos, P & Stewart, AK 2011, 'Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma', Cancer Chemotherapy and Pharmacology, vol. 67, no. 1, pp. 57-67. https://doi.org/10.1007/s00280-010-1283-3
Reece, Donna E. ; Sullivan, Dan ; Lonial, Sagar ; Mohrbacher, Ann F. ; Chatta, Gurkamal ; Shustik, Chaim ; Burris, Howard ; Venkatakrishnan, Karthik ; Neuwirth, Rachel ; Riordan, William J. ; Karol, Michael ; Von Moltke, Lisa L. ; Acharya, Milin ; Zannikos, Peter ; Stewart, Alexander Keith. / Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 1. pp. 57-67.
@article{f55c70e40a8a4ecc8f807f26db106947,
title = "Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma",
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 (102-112 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.",
keywords = "Bortezomib, Multiple myeloma, Pharmacodynamics, Pharmacokinetics, Proteasome inhibition",
author = "Reece, {Donna E.} and Dan Sullivan and Sagar Lonial and Mohrbacher, {Ann F.} and Gurkamal Chatta and Chaim Shustik and Howard Burris and Karthik Venkatakrishnan and Rachel Neuwirth and Riordan, {William J.} and Michael Karol and {Von Moltke}, {Lisa L.} and Milin Acharya and Peter Zannikos and Stewart, {Alexander Keith}",
year = "2011",
month = "1",
doi = "10.1007/s00280-010-1283-3",
language = "English (US)",
volume = "67",
pages = "57--67",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma

AU - Reece, Donna E.

AU - Sullivan, Dan

AU - Lonial, Sagar

AU - Mohrbacher, Ann F.

AU - Chatta, Gurkamal

AU - Shustik, Chaim

AU - Burris, Howard

AU - Venkatakrishnan, Karthik

AU - Neuwirth, Rachel

AU - Riordan, William J.

AU - Karol, Michael

AU - Von Moltke, Lisa L.

AU - Acharya, Milin

AU - Zannikos, Peter

AU - Stewart, Alexander Keith

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

KW - Bortezomib

KW - Multiple myeloma

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Proteasome inhibition

UR - http://www.scopus.com/inward/record.url?scp=78651096626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651096626&partnerID=8YFLogxK

U2 - 10.1007/s00280-010-1283-3

DO - 10.1007/s00280-010-1283-3

M3 - Article

C2 - 20306195

AN - SCOPUS:78651096626

VL - 67

SP - 57

EP - 67

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -