PMID- 34750990 OWN - NLM STAT- MEDLINE DCOM- 20220322 LR - 20220322 IS - 2163-8306 (Electronic) IS - 2163-8306 (Linking) VI - 10 IP - 12 DP - 2021 Dec TI - Population pharmacokinetics of liposomal irinotecan in patients with cancer and exposure-safety analyses in patients with metastatic pancreatic cancer. PG - 1550-1563 LID - 10.1002/psp4.12725 [doi] AB - 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. CI - (c) 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Brendel, Karl AU - Brendel K AD - Ipsen, Les-Ulis, France. FAU - Bekaii-Saab, Tanios AU - Bekaii-Saab T AD - Mayo Clinic, Phoenix, Arizona, USA. FAU - Boland, Patrick M AU - Boland PM AD - Roswell Park Cancer Institute, Buffalo, New York, USA. FAU - Dayyani, Farshid AU - Dayyani F AD - University of California Irvine, Orange, California, USA. FAU - Dean, Andrew AU - Dean A AD - St John of God Hospital Subiaco, Perth, Western Australia, Australia. FAU - Macarulla, Teresa AU - Macarulla T AD - Vall d Hebron University Hospital, Vall d Hebron Institute of Oncology, Barcelona, Spain. FAU - Maxwell, Fiona AU - Maxwell F AD - Ipsen, Abingdon, UK. FAU - Mody, Kabir AU - Mody K AD - Mayo Clinic, Jacksonville, Florida, USA. FAU - Pedret-Dunn, Anna AU - Pedret-Dunn A AD - Ipsen, Abingdon, UK. FAU - Wainberg, Zev A AU - Wainberg ZA AD - Ronald Regan UCLA Medical Center, Los Angeles, California, USA. FAU - Zhang, Bin AU - Zhang B AD - Ipsen, Cambridge, Massachusetts, USA. LA - eng SI - ClinicalTrials.gov/NCT02551991 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Clinical Trial, Phase III PT - Journal Article DEP - 20211120 PL - United States TA - CPT Pharmacometrics Syst Pharmacol JT - CPT: pharmacometrics & systems pharmacology JID - 101580011 RN - 0 (Antineoplastic Agents) RN - 0 (Liposomes) RN - 7673326042 (Irinotecan) RN - EC 2.4.1.- (UGT1A1 enzyme) RN - EC 2.4.1.17 (Glucuronosyltransferase) SB - IM MH - Antineoplastic Agents/administration & dosage/adverse effects/*pharmacokinetics/*therapeutic use MH - Carcinoma, Pancreatic Ductal/*drug therapy/pathology MH - Diarrhea/chemically induced MH - Female MH - Genotype MH - Glucuronosyltransferase/genetics MH - Humans MH - Irinotecan/administration & dosage/adverse effects/*pharmacokinetics/*therapeutic use MH - Liposomes/chemistry MH - Logistic Models MH - Male MH - Metabolic Clearance Rate MH - Models, Biological MH - Neoplasm Metastasis MH - Neutropenia/chemically induced MH - Pancreatic Neoplasms/*drug therapy/pathology PMC - PMC8674005 COIS- K.B. is a full-/part-time employee of Ipsen. T.B.-S. has received advisory/consultancy fees from: 1Globe Health Institute, AbGenomics, Amgen, Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, Celgene, Clovis Oncology, Eli Lilly, Exelixis, Genentech, Immuneering, Imugene, Incyte, Ipsen, Merck, Pancreatic Cancer Action Network (PanCAN), Seattle Genetics, Sobi, Sun BioPharma, Treos Bio. P.M.B. has received research grants/funding from: Advaxis, Bayer, Boehringer Ingelheim, Boston Biomedical, Cascadian Therapeutics, Genentech, Merck; has received advisory/consultancy fees from: Bayer, Merrimack Pharmaceuticals; and honoraria from: Sirtex Medical. F.D. has received institutional research grants/funding from: Amgen, AstraZeneca, Bristol Myers Squibb, Exelixis, Ipsen, Taiho Pharmaceutical; has received advisory/consultancy fees from: Eisai, Exelixis, Foundation Medicine, Genentech, Ipsen, Natera (Signatera), QED Therapeutics; speaker bureau/expert testimony: Amgen, Deciphera Pharmaceuticals, Eisai, Exelixis, Ipsen, Natera (Signatera), Sirtex Medical; and their spouse/financial dependent is a full-/part-time employee of: Roche Diagnostics. A.D. has partaken in non-remunerated advisory/consultancy activities for: Shire, Specialised Therapeutics; and has received compensation for travel/accommodation/expenses from: Amgen. T.M. has received research grants/funding from: Agios, ASLAN Pharmaceuticals, AstraZeneca, Bayer, Biogen, Celgene, Eli Lilly, Genentech, Halozyme Therapeutics, Immunomedics, Merrimack Pharmaceuticals, Millennium Pharmaceuticals, Novartis, Novocure, OncoMed Pharmaceuticals, Pfizer, Pharmacyclics, Roche; has received fees from: Eli Lilly, Ipsen, Roche, Sanofi, Sanofi Genzyme, Shire, Tesaro; has received advisory/consultancy fees from: Baxalta, Celgene, H3 Biomedicine, Incyte, QED Therapeutics, Sanofi Genzyme, Servier, Shire; has provided speaker bureau/expert testimony for: Celgene, Sanofi, Shire; and has received compensation for travel/accommodation/expenses from: Bayer, H3 Biomedicine, Merck, Sanofi. F.M. is a full-/part-time employee and owner of shares/stocks/stock options of Ipsen. K.M. has received research grants/funding from: Agios, ArQule, AstraZeneca, Genentech, Incyte, National Cancer Institute of the National Institutes of Health award # NCI/NIH P50 CA210964, Puma Biotechnology, Senhwa Biosciences, Taiho Pharmaceutical; and has received advisory/consultancy fees from: AstraZeneca, Bayer, Celgene, Eisai, Exelixis, Ipsen, Merrimack Pharmaceuticals, Vicus Therapeutics. A.P.-D. is a full-/part-time employee of: Ipsen. Z.A.W. has received institutional research grants/funding from: Five Prime Therapeutics, Ipsen, Novartis, Plexxikon; and has received advisory/consultancy fees from: AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, Five Prime Therapeutics, Ipsen, Merck, QED Therapeutics. B.Z. is a full-/part-time employee and owner of shares/stocks/stock options of Ipsen; and received licensing/royalties from Ipsen. Funding information: This study was sponsored by Ipsen. EDAT- 2021/11/10 06:00 MHDA- 2022/03/23 06:00 PMCR- 2021/12/01 CRDT- 2021/11/09 07:21 PHST- 2021/06/23 00:00 [revised] PHST- 2021/01/15 00:00 [received] PHST- 2021/08/16 00:00 [accepted] PHST- 2021/11/10 06:00 [pubmed] PHST- 2022/03/23 06:00 [medline] PHST- 2021/11/09 07:21 [entrez] PHST- 2021/12/01 00:00 [pmc-release] AID - PSP412725 [pii] AID - 10.1002/psp4.12725 [doi] PST - ppublish SO - CPT Pharmacometrics Syst Pharmacol. 2021 Dec;10(12):1550-1563. doi: 10.1002/psp4.12725. Epub 2021 Nov 20.