Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

Abstract

Nanoliposomal irinotecan (nal‐IRI) is a liposomal formulation of irinotecan with a longer half‐life (t1/2), 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 Cavg 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 70 mg/m2 (free‐base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI‐1 study

“…Conversely, grade ≥3 diarrhea occurred less frequently in Asian patients compared with patients in the overall safety population (3.0% vs 12.8%). It has been previously shown that Asian race is a significant predictive factor for neutropenia among Asian patients receiving nal‐IRI . Although the incidence of grade ≥3 neutropenia was increased with nal‐IRI+5‐FU/LV treatment in the Asian population, only one case of treatment discontinuation was reportedly as a result of neutropenia.…”

“…In a population PK study of nal‐IRI, the incidence of grade 3‐4 neutropenia and diarrhea was significantly associated with plasma C max of unencapsulated SN‐38 (uSN‐38) and total irinotecan (tIRI), respectively . Interestingly, Asian patients were found to have significantly higher uSN‐38 C max and lower tIRI levels than the Caucasian population .…”

“…Regional differences in treatment outcomes have been observed in pancreatic cancer, and other diseases (eg, advanced gastric cancer) . Previous work has also indicated differences in drug metabolism affecting the plasma concentration of SN‐38 and irinotecan after nal‐IRI treatment between patients of East Asian ethnicity and Caucasian ethnicity . It was reported that Asian patients had a significantly higher mean maximum plasma concentration (C max ) of unencapsulated SN‐38 and a lower C max of total irinotecan after dosing with nal‐IRI compared with Caucasian patients, which was associated with increased grade 3 or 4 neutropenia and decreased grade 3 or 4 diarrhea in Asian versus Caucasian patients .…”

“…Previous work has also indicated differences in drug metabolism affecting the plasma concentration of SN‐38 and irinotecan after nal‐IRI treatment between patients of East Asian ethnicity and Caucasian ethnicity . It was reported that Asian patients had a significantly higher mean maximum plasma concentration (C max ) of unencapsulated SN‐38 and a lower C max of total irinotecan after dosing with nal‐IRI compared with Caucasian patients, which was associated with increased grade 3 or 4 neutropenia and decreased grade 3 or 4 diarrhea in Asian versus Caucasian patients . Therefore, we carried out a post‐hoc subgroup analysis of the NAPOLI‐1 study assessing the efficacy and safety of nal‐IRI+5‐FU/LV in Asian patients treated at Asian centers, the results of which are presented here.…”

Turning cold tumors into hot tumors: harnessing the potential of tumor immunity using nanoparticles

“…More recently, in the Napoli-1 trial, liposomal irinotecan associated with LV-5-FU led to 18% of severe hematological toxicities, a figure markedly lower than the incidence of this toxicity when standard irinotecan is associated with 5-FU, such as the FolFiri regimen [28]. Finally, by sparing hematologic progenitors, nanoparticles can be indirectly further helpful in patients scheduled for immunotherapy, by reducing the need to use antibiotics in patients.…”