Liposomes pharmacokinetic modelling

Liposomal doxorubicin is an irritant, not a vesicant, and is dosed differently from doxorubicin, so clinicians need to be very careful when prescribing these two drugs. The pharmacokinetics of liposomal doxorubicin are best described by a two-compartment model, with a terminal half-life of 30 to 90 hours.20 Liposomal doxorubicin has shown significant activity in the treatment of breast and ovarian cancer, along with multiple myeloma and Kaposi s sarcoma. Side effects include mucositis, myelosuppression, alopecia, and palmar-plantar erythrodysesthesia. The liposomal doxorubicin may be less cardiotoxic than doxorubicin. 

Webb MS, Harasym TO, Masin D, Bally MB, Mayer LD. Sphingomyelin-cholesterol liposomes significantly enhance the pharmacokinetic and therapeutic properties of vincristine in murine and human tumour models. Br J Cancer 1995 72 896. 

Webb MS, Boman NL, Wiseman DJ, et al. Antibacterial efficacy against an in vivo Salmonella typhimurium infection model and pharmacokinetics of a liposomal ciprofloxacin formulation. Antimicrob Agents Chemother 1998 42 45. 

Further modifications of the liposomal composition have led to an improved formulation of the cationic liposomes containing raf ASO (md-LErafAON). The md-LErafAON formulation exhibits superior safety and pharmacokinetic profiles and is an effective anti-tumor agent in a human prostate tumor xenograft model. 

Arnold, R. D., Mager, D. E., Slack, J. E., and Straubinger, R. M. (2005), Effect of repetitive administration of Doxorubicin-containing liposomes on plasma pharmacokinetics and drug biodistribution in a rat brain tumor model, Clin. Cancer Res., 11, 8856-8865. 

Harashima, H. Tsuchihashi, M. Lida, S. Doi, H. Kiwada, H. Pharmacokinetic/pharmacodynamic modeling of antitumor agents encapsulated into liposomes. Adv. Drug Deliv. Rev. 1999, 40 (1-2), 39-61. 

A suitable animal model can be used for in vivo pharmacokinetic assessment of a topically applied elastic liposome formulation. Rats and mice are most common but tend to provide an over-estimate compared to human skin as the skin is more permeable. Piglets provide a closer approximation to human skin permeability and have been used for some evaluations of elastic liposomes (9, 34). Appropriate animal ethics committee approval is required. A generalised protocol is outlined in the following section but there can be considerable variation depending on the complexity of information sought, i.e., if the determination of distribution into tissues is required in addition to absorption into the circulation ... 

The pharmacokinetics of thalidasine in a polyphase liposome preparation and in aqueous solution were determined by HPLC in mice following intravenous injection. The blood drug concentration curve fit a two-compartment open model, with the distribution and elimination half-lives being 3.52 and 23.58 minutes, respectively, for the liposome preparation, and 1.293 and 11.12 minutes, respectively, for the aqueous solution [149]. 

Harrington, K. J., Rowlinson-Busza, G., Syrigos, K. N., Uster, P. S., Abra, R. M., Stewart, J. S. Bio-distribution and pharmacokinetics of (lll)ln-DPTA-labeled pegylated liposomes in a human tumour xenograft model implications for novel targeting strategies. Br. J. Cancer lim, 83, 232-238. 

Gabizon, A., Tzemach, D., Mak, L., Bronstein, M., Horowitz, A. T. Dose dependency of pharmacokinetics and therapeutic efficacy of pegylated liposomal doxorubicin (Doxil) in murine models. J. Drug Target 2002, 10(1), 539-548. 

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