Pharmacokinetics of Pegylated Liposomal Doxorubicin Administered by Intraoperative Hyperthermic Intraperitoneal Chemotherapy to Patients with Advanced Ovarian Cancer and Peritoneal Carcinomatosis

Abstract

ABSTRACT:The pharmacokinetics of pegylated liposomal doxorubicin (PLD) were investigated in 17 women undergoing intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian cancer and peritoneal carcinomatosis. HIPEC was performed immediately after completing debulking surgery, which included a number of peritonectomy procedures. PLD was injected and allowed to equilibrate in peritoneal cavity filled with 4 liters of physiological solution and stabilized at 42°C; next, the outflow line was opened and perfusion proceeded for 1 h. PLD was stable in peritoneal perfusate and plasma. During HIPEC, PLD peritoneal perfusate/plasma gradients averaged ϳ600 or >1000 for peak concentration or area under the curve. After HIPEC, PLD plasma levels remained stable or decreased. Biopsy samples of residual normal peritoneum or ovarian carcinomatosis were collected at the end of HIPEC and were shown to contain free doxorubicin. Correlating PLD decrements in peritoneal perfusate with plasma exposure to PLD or peritoneal deposition of free doxorubicin showed that the former occurred during preperfusional equilibration of PLD in peritoneal cavity, whereas the latter occurred during 1 h of perfusion. Plasma exposure to PLD correlated negatively with the number of peritonectomy procedures performed during surgery, whereas peritoneal deposition of free doxorubicin correlated positively. Taken together, these results show that PLD administered by intraoperative HIPEC undergoes limited systemic diffusion and releases active free doxorubicin in peritoneum exposed to ovarian carcinomatosis. PLD pharmacokinetics seem to be influenced by peritonectomy procedures.

Effect of Liposomal Doxorubicin in Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC)

“…Performing PIPAC with LD might increase its overall efficacy by means of improving penetration into the tissue. This has been indicated by previously analyzing the effect of LD on HIPEC 6 . Theoretically, LD is assumed to have a higher penetrating effect and leads to higher cytotoxicity after PIPAC, provided how LD interacts with the peritoneal tissue after PIPAC.…”

“…However, this could be complicated by the fact that intraperitoneal liposomal particles are in partial systemically absorbed. Findings indicate that liposomal particles that are not initially absorbed by the peritoneum will, after some time, be drained by the lymphatic ducts into systemic circulation 29 or finally absorbed at surgical resection sites following cytoreductive surgery 6 .…”

“…Despite improvements in PIPAC treatment, the overall outcome of patients with PM remains poor. Alternative drug compositions and therapeutic particles are currently being studied for the treatment of PM 5 , 6 .…”

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

“…With a dose of 15-35 mg/m 2 , a limited toxicity has been observed. In some centres, pegylated liposomal doxorubicin has been used for intraperitoneal administration because of its more favourable pharmacokinetics (peritoneal to plasma AUC ratio: ≥ 1,100) and higher uptake in tumour nodules [4,87,88]. In in vitro and in vivo studies on liposome-encapsulated doxorubicin, hyperthermia increased the drug's release, rose tumour uptake of liposome-encapsulated adriamycin but not of free doxorubicin and improved its antitumour activity [4,89].…”

Overview of the optimal perioperative intraperitoneal chemotherapy regimens used in current clinical practice

“…Doxorubicin was considered a candidate for IP application based on its wide in vitro and in vivo activity against a broad range of malignancies, its slow clearance from the peritoneal compartment due to the high molecular weight of the hydrochloride salt, its favorable AUC ratio of IP to IV concentration times of 230 [18,[62][63][64][65][66]. More recently PEGylated liposomal doxorubicin has generated interest for HIPEC application due to its favorable pharmacokinetics [67,68]. [69].…”