title: Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.
abstract: OBJECTIVE
  The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs.
  
  
  METHODS
  Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0-168hafter Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression.
  
  
  RESULTS
  The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (Cmax), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 Cmaxof 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 Cmaxof 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5-3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses.
  
  
  CONCLUSIONS
  EP administration avoids both high SN38 Cmaxvalues and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.
authors.affiliation: Department of Clinical Pharmacology, Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.
authors.forename: S Kenneth
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Department of Toxicology, Nektar Therapeutics, San Francisco, CA, USA.
authors.forename: Theresa D
authors.initials: TD
authors.lastname: Sweeney
authors.affiliation: Department of Toxicology, Nektar Therapeutics, San Francisco, CA, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Clinical Pharmacology, Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA. uhoch@nektar.com.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.affiliation: Department of Clinical Pharmacology, Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA, 94158, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eldon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000633:toxicity*; D015994:Incidence; D000077146:Irinotecan; D008297:Male; D009503:Neutropenia / Q000139:chemically induced*; D011092:Polyethylene Glycols / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D011092:Polyethylene Glycols; D000077146:Irinotecan; C581703:etirinotecan pegol; D002166:Camptothecin
keywords: Breast cancer; Etirinotecan pegol; Irinotecan; NKTR-102; Neutropenia; SN38