PIPAC paclitaxel: A systematic and peritoneal tissue pharmacokinetic study in swine

Annals of Oncology(2019)

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摘要
Introduction: Peritoneal carcinomatosis is a distressing disease with current standard palliative chemotherapy typically producing disappointing results. PIPAC is an innovative method of delivering chemotherapy directly to the peritoneum, aiming to achieve a homogenous and deeper drug penetration. To date, most trials use cisplatin with doxorubicin, or oxaliplatin alone with promising results. We aim to evaluate the pharmacokinetics (PK) and peritoneal tissue drug concentration of paclitaxel, as well as its short term safety profile, when administered via PIPAC in a swine model, to guide future clinical trials. Methods: PIPAC paclitaxel was administered at the starting dose of 60 mg/m2. This was followed by intravenous (IV) administration of the same dose on Day 7 to provide a control for comparison in the same subject. We had planned to investigate 3 dose levels, with 3 pigs for each dose level. As the eighth subject had treatment interrupted due to a hypersensitivity reaction, we expanded the last cohort. Safety and toxicity were evaluated by clinical assessment and with blood counts and biochemistry. Blood samples were collected for pharmacokinetic analysis after drug administration. 4-quadrant peritoneal and omental biopsies were taken before and after the PIPAC procedure. The pig was euthanised after the last blood collection on Day 9. The concentration of paclitaxel in plasma and homogenized tissue was determined by a validated LC-MS/MS method. Results: 12 pigs underwent trial procedures. Systemic exposure to paclitaxel is lower when administered via PIPAC compared to intravenous infusion. Linear pharmacokinetic property is demonstrated when paclitaxel is given by PIPAC, while IV paclitaxel shows non-linearity. In addition, there is a proportional increase in concentration in tissue with increasing doses of PIPAC paclitaxel (r > 0.97). A favorable toxicity profile was seen with PIPAC paclitaxel, particularly at the lower doses (≤ 30 mg/m2). The most common adverse event was neutropenia which was observed to be dose-dependent. One subject experienced grade 2 hypersensitivity reaction during IV paclitaxel administration and one death occurred during the PIPAC procedure. Conclusion: This comprehensive pharmacokinetic study extends our knowledge of peritoneal drug absorption when delivered via the novel PIPAC technique. Both plasma and tissue paclitaxel pharmacokinetic results support that PIPAC paclitaxel shows a linear pharmacokinetic property. While toxicity profile is favorable, standard precautions and monitoring have to be taken when commencing clinical trials in light of the expected adverse events.
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关键词
pharmacokinetic study,peritoneal tissue,swine
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