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.

Keywords: Breast cancer; Etirinotecan pegol; Irinotecan; NKTR-102; Neutropenia; SN38.

Fig. 1

Plasma SN38 concentration–time profiles in dogs by dose group. Dogs for each treatment group were split equally between genders. The high-dose (40/25) etirinotecan pegol animals were treated at 40 mg/kg for the first two treatments (Days 1 and 8) and were then dosed at 25 mg/kg on Days 15 and 22 due to severe adverse clinical signs and mortalities observed on Day 8. However, for two animals in the first replicate, the dose level was decreased to 25 mg/kg only for Day 22, since they were dosed on Day 15 prior to the decision to change the dose level

Fig. 2

Comparison of SN38 C _max (top) and AUC_0-168h (bottom), by study day, treatment, and dose level

Fig. 3

Observed fraction of dogs with neutropenia by SN38 C _max (top) and AUC_0–168h (bottom). Percentages are computed based on number of dogs within the bin range. *In the 20–50 ng/mL C _max range, the dogs that were given 25 mg/kg irinotecan and died prior to their neutrophil levels falling below 2 × 10⁹/L were not counted as neutropenic. Majority of the dogs in 25 mg/kg irinotecan died prior to their Day 22 dose

Fig. 4

Logistic regression model showing the probability of neutropenia as a function of SN38 C _max. Black and gray points represent C _max values after etirinotecan pegol and irinotecan once-weekly administration and whether neutropenia was observed (p = 1) or not (p = 0). The blue-shaded area represents SN38 C _max range after 25 mg/kg etirinotecan pegol and the red-shaded area represents SN38 C _max range after 20 mg/kg irinotecan, both administered once per week

Fig. 5

Visual predictive check comparing the predicted fraction of dogs with neutropenia from the logistic regression model (top) within each SN38 C _max bin with the actual fraction of dogs with neutropenia within the pre-specified bin range (bottom)