Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.

Autor: Sy, S., Sweeney, Theresa, Ji, Chunmei, Hoch, Ute, Eldon, Michael, Sy, S Kenneth, Sweeney, Theresa D, Eldon, Michael A
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Zdroj: Cancer Chemotherapy & Pharmacology; Jan2017, Vol. 79 Issue 1, p57-67, 11p
Abstrakt: Purpose: 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 AUC0-168h after 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 (C max), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 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 C max of 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 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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