DESCRIPTION (provided by applicant): The staggering number of people afflicted with and dying from malaria is well-recognized, as is the ongoing spread of drug-resistance. Although many fewer patients have African trypanosomiasis (sleeping sickness), this infection is uniformly fatal if not treated and current therapies are toxic, expensive, and require parenteral administration. Safe and effective treatments for both diseases are urgently needed. Given the limited resources available to tackle these problems it is critical to identify strategies that maximize efficacy, minimize the likelihood of resistance, and reduce the time required to develop new agents. Pivotal in all of this is the rational application of pharmacokinetic/pharmacodynamic (PK/PD) relationships. The proposed work will utilize a novel in vitro perfusion system that exposes Plasmodium falciparum or Trypanosoma brucei brucei to constantly changing drug concentrations, akin to dynamic pharmacokinetics in vivo. Experiments utilizing this apparatus have revealed that antimalarial activity may be governed in a class-wide fashion by either concentration or time of exposure, and that this governance is independent of 'static or 'cidal activity. Similar findings pertain for antitrypanosomals. Aim 1 wil use traditional integrative analysis to determine whether the reported success (or failure) of experimental drug leads in animals can be explained, at least in part, by match (or mismatch) of PK governance with obtained in vivo kinetics. Aim 2 will explore the pharmacokinetic factors that regulate the efficacy of clinically important antimalarial and antitrypanosomal combination therapies, to obtain a better understanding of the overarching PK drivers of combination efficacy. Aim 3 PK/PD modeling experiments will deploy, solo and in combination, experimental antimalarial drugs against P. falciparum in vitro. Parasites will be exposed to dynamically changing drug concentrations in kinetic regimens derived from Phase I clinical trials. PD endpoints will include time-kill curves, lag time, 99.9 percent clearance time, and drug sensitivit of surviving parasites. Fully parametric analysis of these studies will include drug interaction an Monte Carlo simulation. The latter will identify optimum dosing regimens for Phase 2 efficacy trials. Although in vitro dynamic PK/PD is new to antiprotozoals, and the experimental methods are innovative, the deliverables of this project are near-guaranteed. Results of this work will provide valuable direction to many aspects of drug development and can also lead to the more rational dosing of existing drugs.

PUBLIC HEALTH RELEVANCE: Malaria and African sleeping sickness pose substantial public health problems and the need for new treatments is widely acknowledged. This project uses a novel experimental system to determine how dynamically changing drug levels govern anti-parasitic action. This information can be used to help with the development of new drugs and to improve the use of existing drugs.