title: Impact of drug formulation and free platinum/cisplatin ratio on hypersensitivity reactions to cisplatin: formulation matters.
abstract: OBJECTIVE
  Use of cisplatin can induce type I hypersensitivity reactions that may also be linked to the quality of the drug utilized. We observed cases of hypersensitivity that appeared to be associated with the brand of cisplatin used. The aim of this study was to compare two different brands of cisplatin in relation to type I hypersensitivity reactions.
  
  
  METHODS
  Brand A was used in a tertiary care teaching hospital until 2012, and use of brand B started from January 2013, when the first hypersensitivity cases were observed. Patients were categorized based on symptom. Cisplatin of both brands was analysed by high-performance liquid chromatography (HPLC) and high-resolution electrospray ionization mass spectrometry (ESI-(+)-MS) and characterized according to US Pharmacopeia.
  
  
  CONCLUSIONS
  There were no cases of hypersensitivity associated with the use of cisplatin brand A, whereas four of 127 outpatients that used cisplatin brand B were affected. The two brands were in accordance with the US Pharmacopeia parameters, and there was no significant difference in the total platinum levels between the two brands when analysed by HPLC. However, high-resolution ESI-(+)-MS analyses show that brand B contains approximately 2.7 times more hydrolysed cisplatin than brand A.
  
  
  CONCLUSIONS
  The increase in the hydrolysed form of cisplatin found in brand B may be the cause of the hypersensitivity reaction observed in a subset of patients. We present the first study of the quality of drugs by high-resolution ESI-(+)-MS. Drug regulatory agencies and manufacturers should consider including measurement of hydrolysed cisplatin as a quality criterion for cisplatin formulations.
authors.affiliation: Department of Clinical Medicine, School of Medical Sciences (FCM), University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: E C
authors.initials: EC
authors.lastname: Pincinato
authors.forename: M B
authors.initials: MB
authors.lastname: Visacri
authors.forename: C M
authors.initials: CM
authors.lastname: de Souza
authors.forename: B T
authors.initials: BT
authors.lastname: Tuan
authors.forename: G B
authors.initials: GB
authors.lastname: Ferrari
authors.forename: D N
authors.initials: DN
authors.lastname: de Oliveira
authors.forename: C R
authors.initials: CR
authors.lastname: Barbosa
authors.forename: R F
authors.initials: RF
authors.lastname: Rodrigues
authors.forename: S
authors.initials: S
authors.lastname: Granja
authors.forename: R F L
authors.initials: RF
authors.lastname: Ambrósio
authors.forename: R R
authors.initials: RR
authors.lastname: Catharino
authors.forename: P C P
authors.initials: PC
authors.lastname: Rosa
authors.forename: C S P
authors.initials: CS
authors.lastname: Lima
authors.forename: P G
authors.initials: PG
authors.lastname: Mazzola
authors.forename: P
authors.initials: P
authors.lastname: Moriel
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002945:Cisplatin / Q000009:adverse effects* / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000517:prevention & control; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010984:Platinum / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D010984:Platinum; D002945:Cisplatin
keywords: adverse drug event; cisplatin; drug safety; hypersensitivity reactions; quality control