Population pharmacokinetics of liposomal irinotecan in patients with cancer and exposure-safety analyses in patients with metastatic pancreatic cancer

• Main Authors: Karl Brendel (Author), Tanios Bekaii‐Saab (Author), Patrick M Boland (Author), Farshid Dayyani (Author), Andrew Dean (Author), Teresa Macarulla (Author), Fiona Maxwell (Author), Kabir Mody (Author), Anna Pedret‐Dunn (Author), Zev A Wainberg (Author), Bin Zhang (Author)
• Format: Book
• Published: Wiley, 2021-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2163-8306; 10.1002/psp4.12725
• Keywords: Therapeutics. Pharmacology; RM1-950
• Source: CPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 12, Pp 1550-1563 (2021)

Abstract 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.