Rotational intraperitoneal pressurized aerosol chemotherapy with paclitaxel and cisplatin: pharmacokinetics, tissue concentrations, and toxicities in a pig model

Abstract

OBJECTIVE: We used paclitaxel and cisplatin, known to be effective in intraperitoneal chemotherapy, in a novel prototype of rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) and evaluated the pharmacokinetics, tissue concentrations, and toxicities in a pig model. METHODS: We developed RIPAC, including the nozzle with the conical pendulum motion, and used 10% of intravenous doses of paclitaxel and cisplatin. We used high-performance liquid chromatography followed by tandem mass spectrometry to analyze serum and tissue concentrations. We applied a non-compartment model to study pharmacokinetics to analyze the time-dependent serum concentrations measured before RIPAC to 48 hours. We evaluated the difference in tissue concentrations between twelve peritoneal regions by the modified peritoneal cancer index. For evaluating toxicities, we observed hepatic and renal function until 4 days after RIPAC. RESULTS: Six pigs underwent RIPAC using paclitaxel (n=3) and cisplatin (n=3). The peak serum concentration (C(max)) and the area under the curve were higher for cisplatin, while the time to the peak serum concentration (T(max)) was longer for paclitaxel. Moreover, the parietal peritoneum showed higher tissue concentrations than the visceral peritoneum, and the ratio of tissue to serum concentrations using C(max) was higher for paclitaxel (172.2-6,237.9) than for cisplatin (0.1-9.3). However, there were no renal and hepatic toxicities after RIPAC with paclitaxel or cisplatin. CONCLUSION: Delayed absorption of paclitaxel sprayed by RIPAC into the peritoneum to the bloodstream may lead to higher tissue concentrations at different regions and lower serum concentrations than cisplatin.