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

Clinical Therapeutics
Karthik VenkatakrishnanGurkamal Chatta

Abstract

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. The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. 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. Twenty-one patients (medi...Continue Reading

References

Jun 16, 2001·Journal of Cellular Biochemistry·S A ShahM P Callery
Jul 16, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Diederik F S KehrerAlex Sparreboom
May 20, 2003·Journal of Clinical Pharmacology·Thorir D BjornssonUNKNOWN Pharmaceutical Research and Manufacturers of America Drug Metabolism/Clinical Pharmacology Technical Working Groups
Jun 27, 2003·The New England Journal of Medicine·Paul G RichardsonKenneth C Anderson
May 13, 2004·Cancer Chemotherapy and Pharmacology·Catherine DutreixMichael Seiberling
Oct 6, 2004·British Journal of Haematology·S JagannathK C Anderson
Mar 15, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Teresa PekolGerald Miwa
May 14, 2005·Critical Reviews in Oncology/hematology·Peter BlowerMatti Aapro
Jun 17, 2005·The New England Journal of Medicine·Paul G RichardsonUNKNOWN Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators
Aug 17, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Vinita UttamsinghLiang-Shang Gan
Sep 2, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·C AghajanianD R Spriggs
Feb 21, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wells A MessersmithDeborah K Armstrong
May 19, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert C KaneRichard Pazdur
Sep 27, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Richard I FisherAndré Goy
Jun 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jens VoortmanGiuseppe Giaccone
Sep 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Robert C KaneRichard Pazdur
Aug 30, 2008·The New England Journal of Medicine·Jesús F San MiguelUNKNOWN VISTA Trial Investigators

❮ Previous
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Citations

Aug 19, 2011·Cancer Chemotherapy and Pharmacology·J PortnowT W Synold
Nov 28, 2012·International Journal of Hematology·Norisato HashimotoShinichiro Okamoto
Oct 19, 2010·Journal of Transplantation·Rajeev RaghavanAbdul Abdellatif
Mar 8, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Patricia M LoRussoPercy Ivy
Apr 6, 2013·Immunotherapy·Alessandra RomanoFrancesco Di Raimondo
Sep 29, 2011·Expert Opinion on Pharmacotherapy·Michel Delforge
Nov 26, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Tadas S VasaitisVincent C O Njar
Jul 11, 2014·Clinical Biochemistry·Takashi OsawaJunichi Kawakami
Sep 30, 2014·Expert Opinion on Pharmacotherapy·Prithviraj BoseSteven Grant
Jun 28, 2015·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Paul L McCormack
Oct 23, 2012·Clinical Lymphoma, Myeloma & Leukemia·Nicole WilsonR Donald Harvey
Jul 6, 2012·The Journal of Surgical Research·Bridget N FahyRomi Ghose
Feb 9, 2013·Blood·K Martin Kortuem, A Keith Stewart
Aug 7, 2019·Clinical Pharmacokinetics·Nikki BlosserDouglas Stewart
Nov 3, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Zhengping WangJeffrey R Infante
Jul 15, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jinfu YangChristopher J Kirk
May 29, 2018·Clinical Pharmacokinetics·Carlyn Rose C TanStefan K Barta
Mar 9, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Stefano FogliRomano Danesi
Aug 21, 2021·Immunopharmacology and Immunotoxicology·Hakan Parlakpinar, Mehmet Gunata
Aug 27, 2021·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Zi-Xuan GuoWei Zhao

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