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

Abstract

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. 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. 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. 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.