Pharmacokinetics, biodistribution, toxicity and therapeutic efficacy of liposomal doxorubicin formulations in mice

Mice bearing the orthotopically implanted 4T1 murine mammary carcinoma were used as a model system to explore the therapeutic and toxicological implications of different dosing schedules and dose intensities of STEALTHRTM liposomal doxorubicin (SL-DXR). The pharmacokinetics, biodistribution, and therapeutic efficacy of SL-DXR were studied as a function of liposome size, drug release rate, dose, and dose intensity. In humans the dose-limiting toxicities of CaelyxRTM (the clinical formulation of SL-DXR) are mucocutaneous, resulting, e.g., in palmar-plantar erythrodysesthesia (PPE). Therefore, the tissue distribution of STEALTHRTM liposomes and total doxorubicin (DXR) into cutaneous tissues (skin and paws) and tumors was determined for naive or orthotopically implanted mice after single or multiple injections of SL-DXR.; Liposomes larger than approximately 150 nm in diameter showed reduced tissue uptake in all tissues and reduced therapeutic activity against the 4T1 murine mammary carcinoma in mice. Compared to liposomes with faster drug release rates, liposomes with slower release rates resulted in higher concentrations of DXR in tissues and had greater therapeutic efficacy against the 4T1 murine mammary carcinoma. In mice receiving four doses of CaelyxRTM (9 mg/kg) in short intervals (q1wk), drug concentrations in cutaneous tissues were sustained at high levels, or increased during the course of the experiment, even though plasma levels returned close to baseline between subsequent doses. Drug accumulation in cutaneous tissues was correlated with the development of PPE-like lesions. Lengthening the dose interval to q2wk resulted in lower concentrations of DXR in cutaneous tissues and fewer PPE-like lesions. When the dose interval was extended to q4wk, drug was cleared from all tissues between doses, but therapeutic activity was reduced compared to q1wk or q2wk dose schedules. For identical dose intensities of CaelyxRTM (9 mg/kg/week), infrequent larger doses appeared to have superior therapeutic activity compared to frequent smaller doses. Overall, the results show that the mouse is a valuable animal model for the development of optimal liposomal drug delivery systems.