Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t(1/2)), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (C-max) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher C-avg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 C-max and diarrhea with tIRI C-max. Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70mg/m(2) (free-base; equivalent to 80mg/m(2) salt base) Q2W over 100mg/m(2) Q3W.