Hon Lyn Tan1, Guowei Kim2, Christopher John Charles3, Renee R Li3, Clarisse Jm Jang4, Asim Shabbir2, Koy Min Chue5, Chia Hui Tai5, Raghav Sundar1, Boon Cher Goh6, Glenn Kunnath Bonney7, Wen Donq Looi8, Esther Sh Cheow9, Jimmy By So10, Lingzhi Wang11, Wei Peng Yong12. 1. National University Cancer Institute, Singapore, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 2. National University Cancer Institute, Singapore, National University Health System, Singapore; University Surgical Cluster, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 3. Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore, Singapore. 4. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 5. University Surgical Cluster, National University Health System, Singapore. 6. National University Cancer Institute, Singapore, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, Singapore. 7. University Surgical Cluster, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Health Innovation and Technology, National University of Singapore, Singapore. 8. Bruker Daltonics, Bruker Singapore Pte Ltd, Singapore. 9. Institute for Health Innovation and Technology, National University of Singapore, Singapore. 10. National University Cancer Institute, Singapore, National University Health System, Singapore; University Surgical Cluster, National University Health System, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: sursbyj@nus.edu.sg. 11. Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, Singapore. 12. National University Cancer Institute, Singapore, National University Health System, Singapore; Cancer Science Institute of Singapore, Singapore.
Abstract
INTRODUCTION: Peritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. MATERIALS AND METHODS: PIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. RESULTS: 12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPAC paclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count <1.0 × 103/μL seen at the highest dose. One pig developed grade 2 hypersensitivity reaction during IV infusion and one death occurred during the PIPAC procedure, likely from anaphylaxis; these are known potential adverse events mandating standard precautions and monitoring. CONCLUSION: PIPAC paclitaxel at 15mg/m2 may be considered for a Phase I study.
INTRODUCTION: Peritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. MATERIALS AND METHODS:PIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. RESULTS: 12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPACpaclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count <1.0 × 103/μL seen at the highest dose. One pig developed grade 2 hypersensitivity reaction during IV infusion and one death occurred during the PIPAC procedure, likely from anaphylaxis; these are known potential adverse events mandating standard precautions and monitoring. CONCLUSION:PIPACpaclitaxel at 15mg/m2 may be considered for a Phase I study.
Authors: Adeline N Boettcher; Kyle M Schachtschneider; Lawrence B Schook; Christopher K Tuggle Journal: Mamm Genome Date: 2021-09-02 Impact factor: 3.224
Authors: Soo Jin Park; Eun Ji Lee; Aeran Seol; Sunwoo Park; Jiyeon Ham; Ga Won Yim; Seung-Hyuk Shim; Whasun Lim; Suk-Joon Chang; Gwonhwa Song; Ji Won Park; Hee Seung Kim Journal: J Gynecol Oncol Date: 2022-05-24 Impact factor: 4.756