title: Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog.
abstract: The erythropoietin analog peginesatide was withdrawn from marketing due to unexpected severe anaphylactic reactions associated with administration of the multi-use formulation. The adverse events occurred rapidly following the first ever administration of the drug with most affected patients becoming symptomatic in less than 30min. This is most consistent with an anaphylactoid reaction due to direct activation of mast cells. Laboratory evaluation was undertaken using rat peritoneal mast cells as the model system. Initial studies showed that high concentrations of the formulated drug as well as formulated vehicle alone could cause mast cell degranulation as measured by histamine release. The purified active drug was not able to cause histamine release whereas the vehicle filtrate and lab created drug vehicle were equally potent at causing histamine release. Individual formulations of vehicle leaving one component out showed that histamine release was due to phenol. Dose response studies with phenol showed a very sharp dose response curve that was similar in three buffer systems. Cellular analysis by flow cytometry showed that the histamine release was not due to cell death, and that changes in light scatter parameters consistent with degranulation were rapidly observed. Limited testing with primary human mast cells showed a similar dose response of histamine release with exposure to phenol. To provide in vivo confirmation, rats were injected with vehicle formulated with various concentrations of phenol via a jugular vein cannula. Significant release of histamine was detected in blood samples taken 2min after dosing at the highest concentrations tested.
authors.affiliation: Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD, USA. Electronic address: James.Weaver@fda.hhs.gov.
authors.forename: James L
authors.initials: JL
authors.lastname: Weaver
authors.affiliation: Division of Pharmaceutical Analysis, OTR/OPQ/CDER/FDA, Silver Spring, MD, USA. Electronic address: mboyne@biotechlogic.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyne
authors.affiliation: Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD, USA. Electronic address: Eric.Pang@fda.hhs.gov.
authors.forename: Eric
authors.initials: E
authors.lastname: Pang
authors.affiliation: Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD, USA. Electronic address: Krishna.Chimalakonda@fda.hhs.gov.
authors.forename: Krishna
authors.initials: K
authors.lastname: Chimalakonda
authors.affiliation: Division of Applied Regulatory Science, OCP/OTS/CDER/FDA, Silver Spring, MD, USA. Electronic address: Kristina.Howard@fda.hhs.gov.
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Howard
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D006397:Hematinics / Q000737:chemistry / Q000633:toxicity*; D006632:Histamine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D016688:Mice, Inbred NOD; D010455:Peptides / Q000737:chemistry / Q000633:toxicity*; D019800:Phenol / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D061251:Primary Cell Culture; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D005079:Excipients; D006397:Hematinics; D010455:Peptides; D019800:Phenol; D006632:Histamine; C556270:peginesatide
keywords: Anaphylactoid; Mast cells; Peginesatide; Phenol