PMID- 20110052
OWN - NLM
STAT- MEDLINE
DCOM- 20100218
LR  - 20190626
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 31 Pt 2
DP  - 2009
TI  - Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and 
      pharmacodynamics of bortezomib in patients with advanced solid tumors: a 
      prospective, multicenter, open-label, randomized, two-way crossover drug-drug 
      interaction study.
PG  - 2444-58
LID - 10.1016/j.clinthera.2009.11.012 [doi]
AB  - BACKGROUND: The proteasome inhibitor bortezomib undergoes oxidative 
      biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 
      identified as a partial, yet potentially important, contributor based on in vitro 
      drug metabolism studies. OBJECTIVE: The aim of this study was to assess the 
      effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) 
      and pharmacodynamics (PD) of bortezomib. METHODS: This was a prospective, 
      multicenter, open-label, randomized, multiple-dose, 2-way crossover study in 
      patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m(2) 
      IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive 
      concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial 
      blood samples were collected over the day-8 dosing interval (immediately prior to 
      bortezomib administration, and from 5 minutes to 72 hours after administration) 
      in cycles 1 and 2 for measurement of plasma bortezomib concentrations for 
      noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. 
      All adverse events (AEs) were recorded during each cycle including serious AEs 
      and all neurotoxicity events for up to 30 days after the last dose of bortezomib. 
      RESULTS: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% 
      white; median body surface area, 2.01 m(2)) were randomized to treatment. Twelve 
      patients completed the protocol-specified dosing and PK sampling in both cycles 1 
      and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based 
      on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib 
      AUC(0-tlast)(AUC from time 0 to last quantifiable concentration) for bortezomib 
      plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032-1.772). 
      Consistent with this observed mean increase in bortezomib exposure, concomitant 
      administration of ketoconazole was associated with a corresponding increase 
      (24%-46%) in the blood proteasome inhibitory effect. CONCLUSION: Concomitant 
      administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a 
      mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: 
      NCT00129207.
CI  - Copyright 2009 Excerpta Medica Inc. All rights reserved.
FAU - Venkatakrishnan, Karthik
AU  - Venkatakrishnan K
AD  - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. 
      karthik.venkatakrishnan@mpi.com
FAU - Rader, Michael
AU  - Rader M
FAU - Ramanathan, Ramesh K
AU  - Ramanathan RK
FAU - Ramalingam, Suresh
AU  - Ramalingam S
FAU - Chen, Eric
AU  - Chen E
FAU - Riordan, William
AU  - Riordan W
FAU - Trepicchio, William
AU  - Trepicchio W
FAU - Cooper, Michael
AU  - Cooper M
FAU - Karol, Michael
AU  - Karol M
FAU - von Moltke, Lisa
AU  - von Moltke L
FAU - Neuwirth, Rachel
AU  - Neuwirth R
FAU - Egorin, Merrill
AU  - Egorin M
FAU - Chatta, Gurkamal
AU  - Chatta G
LA  - eng
SI  - ClinicalTrials.gov/NCT00129207
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Antifungal Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Pyrazines)
RN  - 69G8BD63PP (Bortezomib)
RN  - R9400W927I (Ketoconazole)
SB  - IM
MH  - Antifungal Agents/pharmacokinetics/*pharmacology/therapeutic use
MH  - Antineoplastic Agents/*pharmacokinetics/pharmacology/therapeutic use
MH  - Area Under Curve
MH  - Boronic Acids/*pharmacokinetics/pharmacology/therapeutic use
MH  - Bortezomib
MH  - Cross-Over Studies
MH  - *Cytochrome P-450 CYP3A Inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Drug Interactions
MH  - Drug Therapy, Combination
MH  - Female
MH  - Humans
MH  - Ketoconazole/pharmacokinetics/*pharmacology/therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Prospective Studies
MH  - Pyrazines/*pharmacokinetics/pharmacology/therapeutic use
EDAT- 2010/01/30 06:00
MHDA- 2010/02/19 06:00
CRDT- 2010/01/30 06:00
PHST- 2009/09/22 00:00 [accepted]
PHST- 2010/01/30 06:00 [entrez]
PHST- 2010/01/30 06:00 [pubmed]
PHST- 2010/02/19 06:00 [medline]
AID - S0149-2918(09)00402-0 [pii]
AID - 10.1016/j.clinthera.2009.11.012 [doi]
PST - ppublish
SO  - Clin Ther. 2009;31 Pt 2:2444-58. doi: 10.1016/j.clinthera.2009.11.012.