title: Drug interaction between itraconazole and bortezomib: exacerbation of peripheral neuropathy and thrombocytopenia induced by bortezomib.
abstract: OBJECTIVE
  To investigate whether a drug interaction exists between bortezomib and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole and/or the CYP2C19 inhibitor lansoprazole that results in increased severity of bortezomib-induced peripheral neuropathy and thrombocytopenia.
  
  
  METHODS
  Retrospective medical record review.
  
  
  METHODS
  Hematology-oncology ward of a university-affiliated hospital in Japan.
  
  
  METHODS
  Six adults with relapsed multiple myeloma who received intravenous bortezomib plus oral dexamethasone as the first course of a 21-day cycle between July 2007 and December 2008. Four of the six patients were treated concomitantly with itraconazole or lansoprazole: two with itraconazole, one with lansoprazole, and one with both itraconazole and lansoprazole.
  
  
  RESULTS
  Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, we identified the presence and graded the severity of peripheral neuropathy and thrombocytopenia before and during each patient's first 21-day course of bortezomib plus dexamethasone therapy. All three patients who received itraconazole experienced new or worsening peripheral neuropathy; they also experienced grade 4 thrombocytopenia. The patient who received lansoprazole alone, as well as the two patients who did not receive itraconazole or lansoprazole, had no changes in either adverse effect. We also evaluated the relationship between peripheral neuropathy and bortezomib plus dexamethasone therapy by using the Naranjo adverse drug reaction probability scale, and a probable relationship was found. We further assessed whether a drug interaction between bortezomib and itraconazole and/or lansoprazole had occurred involving the CYP3A4 and/or the CYP2C19 pathways, respectively-resulting in increased severity of the bortezomib-induced peripheral neuropathy and thrombocytopenia-by using the Horn drug interaction probability scale. We found that the occurrence of this drug interaction was strongly supported.
  
  
  CONCLUSIONS
  Itraconazole appears to exacerbate peripheral neuropathy and thrombocytopenia induced by bortezomib; however, the mechanism of this drug interaction is unknown. Clinicians should closely monitor for bortezomib-induced adverse effects when itraconazole, or any other potent CYP3A4 inhibitor, is administered concomitantly with bortezomib.
authors.affiliation: Department of Pharmacy, Mie University Hospital, Tsu, Mie, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Miki
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujieda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Masuya
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Katayama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuda
mesh_terms: D000328:Adult; D000368:Aged; D001897:Boronic Acids; D000069286:Bortezomib; D002986:Clinical Trials as Topic; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D011719:Pyrazines; D012189:Retrospective Studies; D055502:Secondary Prevention; D013921:Thrombocytopenia / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D017964:Itraconazole; D000069286:Bortezomib; D003907:Dexamethasone