Pharmacokinetic and tissue distribution advantages of intraperitoneal oxaliplatin over systemic delivery: a swine model comparison of PIPAC and HPIPAC.

BACKGROUND

Peritoneal metastases are a common manifestation with a dismal prognosis in advanced gastric cancer. Systemic chemotherapy has limited efficacy in this setting due to poor drug penetration into the peritoneum. Intraperitoneal (IP) chemotherapy techniques such as Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and its hyperthermic variant, Hyperthermic Pressurized Intraperitoneal Aerosol Chemotherapy (HPIPAC), have emerged as targeted delivery methods to enhance peritoneal drug exposure while reducing systemic toxicity. This study compares the pharmacokinetics, tissue distribution, and peritoneal penetration of oxaliplatin administered via intravenous (IV) injection versus intraperitoneal chemotherapy using aerosolized drug delivery techniques, including PIPAC and HPIPAC.

METHODS

In a swine model (n = 19), oxaliplatin was administered via IV (n = 5), PIPAC (n = 7), or HPIPAC (n = 7). Plasma oxaliplatin levels were measured at 14 time points over 6 h using liquid chromatography–tandem mass spectrometry. Tissue concentrations and tissue-to-plasma ratios were determined for major organs. Drug penetration into the peritoneum was visualized via matrix-assisted laser desorption/ionization mass spectrometry imaging.

RESULTS

IV delivery resulted in rapid systemic exposure but minimal peritoneal concentrations (66.5 ng/mg). PIPAC and HPIPAC significantly enhanced peritoneal tissue concentration (5310.0 ng/mg and 2313.8 ng/mg, respectively) with markedly lower systemic exposure. The depth of tissue penetration was greater with IP delivery, with HPIPAC reaching an average of 2.69 mm.

CONCLUSIONS

Compared to systemic IV chemotherapy, intraperitoneal delivery using aerosolized oxaliplatin under pressurized capnopneumoperitoneum achieved superior peritoneal drug concentration, deeper tissue penetration, and reduced systemic exposure. These findings validate PIPAC and HPIPAC as feasible and potential modalities for treating peritoneal metastases in gastric cancer.