PHARMACODYNAMICS OF PYRONARIDINE IN COMBINATION WITH CURRENT ANTIMALARIALS IN A CYTOCIDAL MURINE MALARIA MODEL
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Date
2018-04-25
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Johns Hopkins University
Abstract
While there has been a progress in understanding P. falciparum genomics, and exciting discoveries of promising leads in the antimalarial pipeline, the efficacies of existing artemisinin combination therapies are threatened by incorrect dosing and non-compliance with duration of dosing regimen, which might hasten the emergence of resistant parasites. Understanding of the effects of drug interactions on combination therapy with existing antimalarial agents may provide useful information such as their mechanism of action, and influence the development of new drug combination. A traditional way of evaluating antimalarial drug efficacy and combined drug interactions has been relying on in vitro drug sensitivity assays using cultured cells. This method measures the rate of suppression or inhibition of parasite growth during 48 – 72 hours in comparison to untreated controls. However, extrapolating in vitro results from cultured parasites to humans remains challenging as cytocidal activity of antimalarials (reduction in absolute parasite numbers) in patients is measured at a high asynchronous parasitemia at close to 1 trillion (per adult).
In this thesis, we adapted a transgenic luciferase reporter, P. berghei ANKA to study cytocidal activity of tafenoquine and pyronaridine in mice for combinations of three current antimalarials, artesunate, amodiaquine, and azithromycin at clinically relevant dosage. We initiated each drug treatment at a high parasitemia (~10%) and followed for 30 days. Three metrics of measures we used in characterizing pharmacodynamic properties are 30-day survival, parasite log reduction over 48 hours, and recrudescent parasitemia (i.e., return to initial parasitemia). We adapted the parasite reduction ratio (PRR), or fractional log reduction in parasitemia as the PRR can be analogous to the killing rate, thus serving as a measure to compare the different intrinsic pharmacodynamic between the drugs in question. Pyronaridine when compared to tafenoquine at the same dose exhibited more potent cytocidal activity with approximately 1,000-fold more reduction in the number of parasite over the single 24-hour parasitic life cycle. Tafenoquine synergized with artesunate. In contrast, additive interactions were evident for pyronaridine in combination with artesunate. In addition, while pyronaridine synergized amodiaquine, differential interactions were shown with azithromycin, suggesting that synergy may only be achieved at certain dose ratios.
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Antimalarial chemotherapy, Plasmodium berghei