Essential PK/PD relationships of antimalarial drugs

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The ever-pressing problem of drug resistance harms individual patients, threatens public health control efforts, and drives costly and time-consuming new drug discovery. For antibacterial and antimycobacterial drugs, dynamic in vitro pharmacokinetic/pharmacodynamic (hollow fiber PK/PD) studies have proven exceedingly valuable for predicting efficacy and selection of resistance and are now an expected component of drug approval packages. This proposal investigates drug therapies, including combinations, for malaria. With previous funding from this grant we established methods that allow dynamic in vitro PK/PD for antiprotozoal drugs, and for several dozen agents have discovered an unambiguous governance by either concentration or time, that is constant over logs of drug exposure. The kinetic driver for an antiprotozoal was not a priori predictable, was unrelated to static/cidal activity or time kill curves and was independent of reversible or irreversible drug action. It was, however, class-wide (e.g., all tested trioxanes were concentration-driven). In vitro findings were prospectively confirmed in murine models (supported by other sources) and retrospectively consistent with published clinical trials data. Methods for deploying two drugs simultaneously, each by its own kinetic pattern, have been established and validated. The proposed experiments will build on this foundation, addressing issues surrounding drug resistance and combination therapies. Studies will feature experimental agents, dihydroartemisinin with additive partner lumefantrine, and atovaquone with synergistic partner proguanil. Resistance studies will be conducted with well- characterized isogenic pairs of wild type cells and their clinically relevant drug resistant mutants and will include mutants with high as well as low degrees of resistance. Aim 1 studies will assess the impact of drugs applied singly, questioning whether, for the same total dose, the pattern of drug pressure (short-lived high pulse vs. constant lower concentration) differentially impacts growth of resistant vs. wild type cells. Aim 2 will feature wild type cells exposed to drug combinations, asking how the pattern of individual partner kinetics affects efficacy of the combination. Aim 3 will then examine the role of partner kinetics against resistant cells, probing the importance of maintaining their concentrations at constant ratio over time, and evaluating the consequence of matching (or not) drug kinetics to their drivers. Results from these inaugural PK/PD studies of antimalarial drug combinations and drug resistance will provide a window into the fundamental PK governance of efficacy (and resistance selection), will provide a template for similar study of other antiprotozoals, will set the stage for dynamic in vitro PK/PDs that model human kinetics vs. parasites, and will provide a new metric for judging experimental and clinically used antiprotozoals.