Pharmacokinetics of intra-arterial applied liposomal encapsulated doxorubicin in liver metastases or hepatocellular carcinoma: A phase I study

Abstract

13523 Background: Doxorubicin has been one of the most widely used anti-neoplastic agents as a single-agent systemic therapy for HCC. Doxorubicin is also used in locoregional therapy approaches. Caelyx (Doxil) is a doxorubicin formulation of polyethylene glycol-coated liposomes. For this new form of doxorubicin, a superior pharmacokinetic profile over that of free doxorubicin is postulated. Blood flow reduction by micro embolization with degradable starch microspheres (DSM; e.g. Spherex, EmboCept) is effective in HCC and liver metastasis. Purpose: Evaluation of the pharmacokinetics (PK) of the encapsulated as well as the released fraction of doxorubicin in addition to the determination of the maximum tolerated dose of intra-arterially applied liposomal encapsulated doxorubicin (Caelyx) in HCC and liver metastases in combination with DSM. Methods: All patients with histologically proven HCC or liver metastases had shown progressive disease when previously treated with systemic chemotherapy. Six dose escalation steps from 15 mg/m2 to 100 mg/m2 were performed with two or three patients in each dose group. Each patient received one single application of Caelyx/DSM. The distribution of Caelyx depended on the tumor size in the left and right liver lobe. For the quantification of Caelyx, doxorubicin, and doxorubicinol, a validated RP-HPLC method with fluorometric detection (excitation wavelength: 470 nm, emission wavelength: 550 nm) was used. Results: PK was calculated for 13 out of 14 treated patients. The mean (terminal) half life for Caelyx was calculated as 3 days, mean residence time about 5 days, the Vss 1.5 l, clearance was determined to be less than 1 ml/min. The increase in peak plasma concentration as well as AUC was linear between 15 and 100 mg/m2 Caelyx. The MTD was reached at a single dose of 100 mg/m2 due to WHO- grade 3 myelosuppression in two patients without further SAE. Conclusions: These first results indicate that hepatic intra arterial chemotherapy with Caelyx in combination with DSM is well tolerated and achieved encouraging responses in patients with liver metastases or HCC. The main PK parameter for Caelyx in combination with DSM did not significantly differ from those obtained after systemic intravenous infusion. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Essex Pharma GmbH, PharmaCept GmbH