Clinical Pharmacokinetic Advantages of New Drug Delivery Methods for the Treatment of Liver Tumours

Abstract

Response rates following systemic chemotherapy for hepatic tumours are disappointing. The drugs used have a narrow therapeutic ratio, which limit the scope for dose escalation of these potentially toxic agents. Therefore, alternative delivery methods that optimise the efficacy of currently available cytotoxic agents have been explored. Several novel approaches have attempted to 'target' treatment so that it reaches the tumour whilst minimising systemic exposure. There is some evidence to suggest that certain agents, including monoclonal antibodies and liposomes, selectively lodge in tumours following intravenous administration. Alternatively, the route of administration may be modified to enhance targeting of the administered drug. Delivery via the hepatic arterial, portal venous, and peritoneal routes as well as drug delivery via direct implantation may provide certain pharmacokinetic advantages. Infusion rates may be adjusted to optimise the pharmacokinetic profile. Chemoembolisation with microspheres, microcapsules or macromolecules might enhance targeting further. Variations in particle characteristics or by modifying hepatic arterial blood flow with vasoactive substances may be used to further refine this technique. The ultimate 'magic bullet', which allows total delivery of treatment to malignant cells whilst eliminating exposure of healthy tissues to these toxic agents, has not been developed as yet. However, currently available techniques allow considerable dose escalation that, whilst not providing a significant survival advantage, certainly improves response rates.

A Novel Method for Preparation of Animal Models of Liver Damage: Liver Targeting of Carbon Tetrachloride in Rats.

“…Therefore, an appropriate animal model in which only the liver is damaged is required to estimate the precise effects of hepatic disorder on drug disposition. Marked progress has been made in drug delivery techniques, 9,10) and their utilization for animal model preparation is expected to reduce damage to nontarget organs. However, to date there have been no reports of the application of such methods for this purpose.…”

Effect of instillation method on the absorption of phenolsulphonphthalein as a model drug from the liver and small intestinal serosal surface in rats

“…For the intraperitoneal administration of liver cancer chemotherapy, the drug solution is expected to distribute preferentially around the diseased region in the liver. Although intravenous, hepatic arterial and portal administration have been attempted as targeted delivery methods (Anderson et al 1994), the administered drug tends to distribute through the entire liver. We have shown previously that direct injection into an organ is not suitable for site-selective drug delivery to the liver with a high blood flow, since directly injected drugs are rapidly cleared from the injection site and enter the systemic circulation (Nishida et al 1994).…”

Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

“…Hepatic metastases from a variety of primary human tumours occur with high frequency, and their presence is usually associated with a low response rate to conventional systemic chemotherapy (Anderson et al, 1994). Efforts to establish innovative drug delivery strategies that improve the efficacy of anti-cancer agents against liver metastases, therefore, are not only desirable but may also produce clinical results more rapidly than the development of new chemical entities (Kim, 1993).…”

“…Efforts to establish innovative drug delivery strategies that improve the efficacy of anti-cancer agents against liver metastases, therefore, are not only desirable but may also produce clinical results more rapidly than the development of new chemical entities (Kim, 1993). Portal vein or hepatic artery infusion of a cytotoxic agent (Anderson et al, 1994), encapsulation of drugs in liposomes (Kim, 1993;Anderson et al, 1994) and livertargeted erythrocytes (Zocchi et al, 1989) are examples of recently employed attempts to increase the anti-tumour efficacy of chemotherapeutic agents against metastatic liver neoplasms.…”