Abstract
PurposeThe 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.MethodsDogs 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.ResultsThe 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 Cmax 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 Cmax 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.ConclusionsEP administration avoids both high SN38 Cmax values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.
Highlights
Irinotecan is the active pharmaceutical ingredient of Camptosar® (Camptothecin-11), a topoisomerase 1 inhibitor widely used as a chemotherapeutic agent
No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg, despite 2.5–3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses
SN38 concentrations after irinotecan administration were below the limit of quantitation after 48 h post-dose, whereas SN38 concentration after EP remained measurable for the duration of assessment (48– 678 h)
Summary
Irinotecan is the active pharmaceutical ingredient of Camptosar® (Camptothecin-11), a topoisomerase 1 inhibitor widely used as a chemotherapeutic agent. Irinotecan has clinical utility, its anti-tumor activity may be limited by its short half-life due to inactivation at physiological pH by the opening of its lactone E-ring and rapid clearance of both parent drug and SN38. The terminal half-life (t1/2) of irinotecan is 9–14 h, while the t1/2 of SN38 is 24–47 h [2,3,4]. The side effect profile of irinotecan is dependent on the mode of administration, Cancer Chemother Pharmacol (2017) 79:57–67 with protracted infusions associated with lower incidences of severe myelosuppression [7,8,9], suggesting that SN38 Cmax rather than duration of exposure contributes to severe hematologic toxicities
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call