Development of miltefosine as an oral treatment for leishmaniasis

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Miltefosine was initially developed as a topical treatment for cutaneous cancers.
• Subsequent development focused on its use in treating leishmaniasis.
• Extensive non-clinical data has been gathered for both indications.

Purpose of the Study:

• To summarize the non-clinical safety and pharmacokinetic profile of Miltefosine.
• To identify potential target organs for toxicity.
• To inform safe clinical use and handling of the drug.

Main Methods:

• Review of existing non-clinical (animal) and clinical study data.
• Analysis of pharmacokinetic parameters, including elimination half-life and distribution.
• Evaluation of reproductive and developmental toxicity studies.

Main Results:

• The gastrointestinal tract is the primary site of toxicity in animals and humans.
• Testis and retina were identified as target organs in rats, but not observed in human clinical studies.
• Miltefosine exhibits a long terminal elimination half-life and is widely distributed, with no in vitro cytochrome P450 metabolism.
• The drug is embryotoxic, fetotoxic, and teratogenic in rats, and embryotoxic/fetotoxic in rabbits.

Conclusions:

• Miltefosine's toxicity profile necessitates careful monitoring, particularly for gastrointestinal effects.
• Reproductive toxicity data indicates contraindication during pregnancy.
• Effective contraception is mandatory for women of childbearing potential during and after treatment.