Pharmacokinetics of the intraperitoneal nanoparticle pegylated liposomal doxorubicin in patients with peritoneal metastases

Abstract

Background: Peritoneal surfaces are a common site for the dissemination of gastrointestinal and gynecologic malignancy. Often, the surgeon can achieve a complete response. Unfortunately, current perioperative chemotherapy regimens fail to maintain control of cancer nodules within the abdomen and pelvis. More effective perioperative chemotherapy is needed.

Materials and methods: The nanoparticle pegylated liposomal doxorubicin (PLD) was instilled directly into the peritoneal space in peritoneal metastases patients following maximal efforts of cytoreductive surgery to resect abdominal and pelvic disease. Pharmacokinetics were determined intraoperatively during hyperthermic intraperitoneal chemotherapy (HIPEC) conditions and postoperatively during early postoperative intraperitoneal chemotherapy (EPIC) at normothermic conditions.

Results: The retention of PLD within the peritoneal tissues over a 90-min HIPEC was only approximately 20% and 180 min of HIPEC 40%. The median area under the curve ratio of peritoneal fluid concentration times time as compared to plasma concentration times was over 1000 and increased with dose escalation from 50 to 100 mg/m2. When PLD was instilled for EPIC, the area under the curve ratios were very similar to the HIPEC but retention of drug within the peritoneal tissues with access to cancer nodules was maintained for 24 h with approximately 80% drug utilization. Adverse events were tabulated and found to be absent. No evidence of peritoneal dysfunction from sclerosis was evident with a 1 year of follow-up.

Conclusions: The nanoparticle PLD is slowly absorbed into the intraperitoneal tissues and not appropriate for HIPEC. EPIC is the preferred methodology for administration.

Keywords: Carcinomatosis; Cytoreductive surgery; Doxorubicin; EPIC; HIPEC; Intraperitoneal; Liposomal doxorubicin; Nanoparticles; Peritoneal metastases.