Absolute Bioavailability of Oxaliplatin After Intraperitoneal Administration by Electrostatic Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC): Systemic Pharmacokinetics of the CRC-PIPAC-II Trial

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) offers a localized palliative treatment option for patients with colorectal peritoneal metastases (CPM), often combined with systemic therapy to maximize anti-tumor efficacy. This study on the pharmacokinetics of oxaliplatin-based PIPAC with electrostatic precipitation (ePIPAC-OX) aimed to determine the absolute bioavailability of oxaliplatin in plasma after ePIPAC-OX with reference to systemic therapy and to gain insights for optimizing therapy. METHODS: This analysis included patients of the recently published CRC-PIPAC-II study, who received three cycles of oxaliplatin-based systemic therapy and ePIPAC-OX for unresectable CPM. Whole-blood and plasma ultrafiltrate samples were collected at five to six time points after both intravenous oxaliplatin and ePIPAC-OX. Pharmacokinetics were analyzed using population modeling. Absolute bioavailability was calculated as the fraction of the Area under the Curve (AUC0-∞) of the systemic oxaliplatin exposure after intraperitoneal administration over the AUC after intravenous administration, corrected for the dose. RESULTS: The study included 18 patients, mostly treated with capecitabine and oxaliplatin (CAPOX) and bevacizumab (15 patients). The median dose-uncorrected AUC of systemic oxaliplatin and ePIPAC-OX in plasma was 165.2 μg*h/mL and 57.4 μg*h/mL, respectively. The median bioavailability of the total concentration and free fraction of oxaliplatin after ePIPAC-OX were both 48 % (interquartile range [IQR] 42-57 %). Dose reduction due to toxicity was required for eight patients (44 %). All the included patients experienced short-term symptoms of acute sensory neuropathy, with eight cases occurring after ePIPAC-OX. CONCLUSION: This is the first study to examine the absolute bioavailability of oxaliplatin administered by ePIPAC-OX in humans, using intra-patient data as a control measurement. The systemic bioavailability of oxaliplatin was substantial after ePIPAC-procedures. Therefore, ePIPAC-OX cannot be considered as solely a local treatment. Future research should take this into account for patients treated with both systemic chemotherapy and ePIPAC-OX as bidirectional therapy.