Cancer chemotherapy and pharmacology · 2025
Pharmacokinetic comparison of cisplatin administration via HIPEC and intravenous infusion in a porcine model.
СтатьяСравнительное исследованиеНазвание и аннотация: Перевод в очереди
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Harlev Christina, Petersen Elisabeth Krogsgaard, Bue Mats, Petersen Lone Kjeld, Lilleøre Johanne Gade, Schmedes Anne Vibeke, Bibby Bo Martin, Stilling Maiken
Аннотация
PURPOSE: Epithelial ovarian cancer (EOC) is associated with high recurrence and poor prognosis. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) offers a locoregional treatment strategy. However, the pharmacokinetics of cisplatin administered via HIPEC compared to intravenous (IV) infusion remain insufficiently characterized. This study aimed to compare local abdominal tissue concentrations and systemic exposure of cisplatin following HIPEC and IV administration in a healthy porcine model using microdialysis.
METHODS: Sixteen healthy Danish Landrace pigs were divided into HIPEC (n = 8) and IV (n = 8) groups. The HIPEC group underwent CRS followed by 90-minute cisplatin-based HIPEC. The IV group received an equivalent cisplatin dose intravenously (100 mg/m²). Microdialysis catheters were placed in the liver, rectum, stomach (superficial and profound layers) and peritoneum. Free cisplatin concentrations were quantified using UPLC-MS/MS.
RESULTS: Within the HIPEC group, cisplatin Cmax and AUC0 - last were significantly higher in the peritoneum compared to other abdominal tissues and plasma. The peritoneal-to-plasma AUC0 - last ratio was 8.7 for HIPEC vs. 1.8 for IV infusion (ratio: 4.92, 95% CI: 3.12-7.78, p < 0.001). Compared to IV infusion, HIPEC achieved significantly higher peritoneal Cmax, while peritoneal AUC0 - last was comparable. In contrast, IV infusion resulted in significantly higher plasma and non-peritoneal tissue exposure. Plasma AUC0 - last was 4.7-fold higher following IV administration compared to HIPEC (95%-CI: 3.0-7.3, p < 0.001).
CONCLUSION: HIPEC concentrates cisplatin within the peritoneum while minimizing systemic distribution, whereas IV administration leads to a broad systemic and less targeted exposure. These findings support the pharmacologic rationale for HIPEC in maximizing local cytotoxicity and minimizing systemic toxicity in EOC treatment.
METHODS: Sixteen healthy Danish Landrace pigs were divided into HIPEC (n = 8) and IV (n = 8) groups. The HIPEC group underwent CRS followed by 90-minute cisplatin-based HIPEC. The IV group received an equivalent cisplatin dose intravenously (100 mg/m²). Microdialysis catheters were placed in the liver, rectum, stomach (superficial and profound layers) and peritoneum. Free cisplatin concentrations were quantified using UPLC-MS/MS.
RESULTS: Within the HIPEC group, cisplatin Cmax and AUC0 - last were significantly higher in the peritoneum compared to other abdominal tissues and plasma. The peritoneal-to-plasma AUC0 - last ratio was 8.7 for HIPEC vs. 1.8 for IV infusion (ratio: 4.92, 95% CI: 3.12-7.78, p < 0.001). Compared to IV infusion, HIPEC achieved significantly higher peritoneal Cmax, while peritoneal AUC0 - last was comparable. In contrast, IV infusion resulted in significantly higher plasma and non-peritoneal tissue exposure. Plasma AUC0 - last was 4.7-fold higher following IV administration compared to HIPEC (95%-CI: 3.0-7.3, p < 0.001).
CONCLUSION: HIPEC concentrates cisplatin within the peritoneum while minimizing systemic distribution, whereas IV administration leads to a broad systemic and less targeted exposure. These findings support the pharmacologic rationale for HIPEC in maximizing local cytotoxicity and minimizing systemic toxicity in EOC treatment.