Pharmacokinetic / Toxicokinetic Characterization of Orally-Active Anti-Parasitic Agents
Effective treatment of human parasitic diseases remains a challenging public health issue, particularly in underdeveloped countries. Such diseases can be fatal if untreated and include visceral leishmaniasis and African trypanosomiasis (a.k.a. African sleeping sickness). Traditional agents used to treat these diseases are effective, however can elicit serious adverse effects. In addition to toxicity concerns, all of these agents must be administered parenterally (due to a low oral bioavailability), which can be especially challenging in remote regions of endemic countries. Taken together, an orally active agent with a low potential for toxicity would have great clinical benefit. The mission of the UNC-led Consortium for Parasitic Drug Development (CPDD), funded by the Bill and Melinda Gates Foundation, is to discover and develop new and safer treatments for human visceral leishmaniasis and African trypanosomiasis. The structural analog of pentamidine, pafuramidine, is an oral prodrug that is biotransformed to the active metabolite, furamidine, via sequential cytochrome P450- and cytochrome b5/b5 reductase-mediated reactions. Pafuramidine completed Phase III clinical trials as treatment for first-stage African trypanosomiasis, showing a cure rate of ~85% and no signs of toxicity. Unexpectedly, during an extended Phase I safety trial in healthy African volunteers, cases of delayed kidney toxicity halted further clinical development. As a result, future drug candidates must be evaluated thoroughly for potential kidney toxicity during pre-clinical stages of development. The CPDD is currently investigating new lead compounds for the treatment of late-stage (CNS) infection, due to the higher urgency relative to first-stage infection. In vitro and in vivo animal studies are ongoing to evaluate the metabolism/transport, pharmacokinetics, efficacy, and potential organ toxicity of these compounds. The knowledge gained will aid in the selection of drug candidates for further development and, ultimately, for advancement to clinical trials as treatment for late-stage African trypanosomiasis.