Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study

Liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, while effectively delivering drug to the tumor. We conducted an open-label phase I study to determine the pharmacokinetic profile of a single dose of liposome-encapsulated doxorubicin (Myocet) in patients with various solid tumors. Safety and tolerability were monitored.

Patients received a single intravenous infusion of Myocet 75 mg/m². Plasma samples were analyzed for concentration of liposome-encapsulated doxorubicin, total doxorubicin, and doxorubicinol.

A total of 18 patients aged 20–73 years (median 60 years) participated; 17 were evaluable for pharmacokinetic analysis. The most common primary tumor was soft tissue sarcoma (22%). Total body clearance for total doxorubicin was 5.6 l/h/m² while the volume (V_ss) was 82 l/m². The terminal half-life was 52.6 h. Based on the AUC and C_max values for total doxorubicin and encapsulated doxorubicin, an estimated 85% of circulating doxorubicin was encapsulated. Doxorubicinol was detected in all patients; the mean AUC was 2.03±1.10 μmol/l/h. The mean 48-h urinary excretion of doxorubicin was 6.44% of the dose. The most common adverse events were nausea (94%), fatigue (78%) and vomiting (67%). Cardiotoxicity (measured as ten-point fall in LVEF to <50%) was observed in one patient. Pharmacokinetic values did not correlate with hematological, laboratory or demographic variables.

The pharmacokinetic profile of Myocet suggests that the liposomal formulation results in a longer half-life with less free drug available for tissue distribution than conventional doxorubicin, consistent with the enhanced therapeutic index observed in clinical studies.