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

Abstract

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 AUC_0–168h 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.

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