PHARMACODYNAMIC ANALYSIS OF P. FALCIPARUM KILL RATES IN MONOTHERAPY CLINICAL TRIALS AND INVESTIGATION OF QUORUM SENSING-DEPENDENCE OF EARLY KILL RATES IN MURINE MODELS
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Date
2018-04-26
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Johns Hopkins University
Abstract
In treating malaria infections, rapid pharmacodynamic kill rates avert death and hinder drug resistance. We explored the recent 4 decades of published P. falciparum monotherapy drug trials featuring over 17,000 patients from 355 study arms from which we could extract pharmacodynamic data related to parasite reduction. Artemisinins represented 36%, methanolquinolines 27%, 4-aminoquinolines 20%, antifolates 10%, and antibiotics 7% of the useable trials. The fold-decrease in parasite count in 48 hours after treatment (PRR) and the time to clear 50% of the parasites (PC50) were robust metrics because either can be used to reliably predict the other. Other metrics like parasite clearance times (time to 90 or 100% clearance) or cure rate have clinical significance and are widely reported but provide little insight into pharmacodynamic rates. The critical first 48-hour PRR was around 5,100 for artesunate, 1,100 for quinine, 3,700 for chloroquine, 840 for sulfadoxine-pyrimethamine, 100 for atovaquone-proguanil, and 2 for clindamycin and azithromycin. After an extended lag, the antibiotics had a maximum PRR of 5,700, leading us to consider the time at which each drug reaches its maximum kill rate. All analyses were performed with the understanding that the trials had wide arrays of covariates such as initial parasitemia. In Plasmodium, physiological changes spurred by quorum sensing at high parasite density could affect drug sensitivity or parasite clearance. To better understand the effects of starting parasite density and quorum sensing on parasite kill rate, mouse models infected with P. berghei ANKA parasites expressing the GFP-luciferase reporter were treated with artesunate, amodiaquine, or pyronaridine at different times following infection. Mice were treated beginning at roughly 10,000, 100,000, or 1,000,000 parasites/µL (during log growth) or on day 6, 8, or 10 after infection (during the plateau phase). In subsequent arms, mice were treated either before or after the projected "inflection point" between the log and plateau phases. In general, mice treated during the plateau cleared parasites slower immediately following treatment, but overall clearance and outcome was not significantly affected. This pattern was most exaggerated in artesunate, but there was also a notable distinction in mice treated with quinolines, especially at low doses.
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malaria, malaria chemotherapy, berghei, parasite reduction ratio, artesunate, amodiaquine, pyronaridine