Essential PK/PD Relationships of Antimalarial and Antitrypanosomal Drugs

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DESCRIPTION (provided by applicant): The staggering numbers of people afflicted with and dying from malaria are well-recognized, as is the ongoing spread of drug-resistant malaria. 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 regimens for malaria and sleeping sickness are urgently needed. Given the limited resources available to tackle this problem it is critical to identify strategies that maximize efficacy and minimize the likelihood of resistance, and that reduce the time required to develop new agents. Pivotal in this is a clear understanding of essential pharmacokinetic/pharmacodynamic (PK/PD) relationships. For anti-infectives in general, the efficacy of a given drug exposure (area under the concentration-time curve, AUC) is mediated either by peak concentration (CMAX) or by time over a minimum effective concentration (TMIC). This property is class-wide and not predictable. Insight into this essential PK/PD relationship can inform many aspects of a drug development program, and also lead to more rational dosing of already-marketed drugs. Remarkably, almost nothing is known about the essential PK/PDs that govern antimalarial and antitrypanosomal drug action. The proposed work will utilize a novel in vitro perfusion system that exposes Plasmodium falciparum or Trypanosoma brucei to constantly changing drug concentrations, mimicking those encountered in humans after drug dosing. The apparatus can be programmed to deliver a given AUC in any desired PK profile, including extremes of CMAX or TMIC. Pilot studies demonstrate that rigorous proof-of-concept PK/PD studies are now possible. In Aim 1 this new system will be used to describe the essential PK/PDs for selected antimalarials, to determine whether these relationships are class-wide, if they correlate with those for bacteria, and how the PK/PD relationship is affected by, and itself affects, drug resistance. Aim 2 will focus on the essential PK/PDs of antitrypanosomal drugs. Though the concept of CMAX- or TMIC-mediated efficacy is new to antiprotozoals, and the experimental method is innovative, the deliverables of this project are near-guaranteed. Results of this work will include a robust well-characterized method for determining the essential PK/PD relationships; first-ever descriptions of the PK/PD requirements for most classes of clinically useful antimalarial and antitrypanosomal drugs and a few experimental agents; and preliminary insights into the possible role of PKs in antimalarial drug resistance. Perhaps most important, it will provide a heretofore missing framework within which antimalarial and antitrypanosomal agents can be judged and used rationally.