Open AccessPopulation pharmacokinetics of liposomal irinotecan in patients with cancer and exposure–safety analyses in patients with metastatic pancreatic cancer
Author(s) -
Brendel Karl,
BekaiiSaab Tanios,
Boland Patrick M,
Dayyani Farshid,
Dean Andrew,
Macarulla Teresa,
Maxwell Fiona,
Mody Kabir,
PedretDunn Anna,
Wainberg Zev A,
Zhang Bin
Publication year - 2021
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12725
Subject(s) - irinotecan , medicine , pharmacokinetics , neutropenia , population , adverse effect , gemcitabine , pancreatic cancer , active metabolite , gastroenterology , oncology , pharmacology , cancer , toxicity , colorectal cancer , environmental health
Liposomal irinotecan is a liposomal formulation of irinotecan, which prolongs circulation of irinotecan and its active metabolite SN‐38. A population pharmacokinetic (PK) model was developed based on data from seven studies ( N = 440). Adequacy of the model was assessed using multiple methods, including visual predictive check. Associations between PK exposure and the incidence of diarrhea (grade ≥3) and neutropenia adverse events (AEs) (grade ≥3) at first event in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) were investigated using logistic regression based on data from two studies (the phase III NAPOLI‐1 [ N = 260] and phase I/II NCT02551991 [ N = 56] trials). The PKs of total irinotecan was described by a two‐compartment model with first‐order elimination, with SN‐38 formed directly by a first‐order constant from the central compartment of irinotecan or after using a transit compartment. Clearance was 17.9 L/week (0.107 L/h) and 19,800 L/week (118 L/h) for total irinotecan and SN‐38, respectively. The UGT1A1*28 7/7 homozygous genotype had no significant impact on SN‐38 clearance. Model evaluation was satisfactory for both irinotecan and SN‐38. The incidence of diarrhea (grade ≥3) at first event was significantly higher with increasing average concentrations of total irinotecan and SN‐38; there was no significant association between an increased risk of neutropenia AEs (grade ≥3) at first event and average SN‐38 concentrations. In summary, the PKs of total irinotecan and SN‐38 after administration of liposomal irinotecan were well‐described by the model. The UGT1A1*28 status had no significant impact on the PKs of liposomal irinotecan.