Research ArticleMalaria

Model System to Define Pharmacokinetic Requirements for Antimalarial Drug Efficacy

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Science Translational Medicine  02 Oct 2013:
Vol. 5, Issue 205, pp. 205ra135
DOI: 10.1126/scitranslmed.3006684

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Drug Dosing from a Dish

The mosquito-borne parasite that causes malaria should be public enemy number one because it kills more children around the world than any other infectious disease. Although antimalarial drugs have been available for many decades, the disease is still prevalent and the most virulent parasite Plasmodium falciparum is acquiring drug resistance at an alarming pace. To aid the discovery of new drugs, Bakshi et al. have constructed an in vitro system in which to grow the parasites that can accelerate new drug discovery. With this culture system, the pharmacokinetic requirements that govern the efficacy of prospective drugs can be extracted and used to prioritize their development.

Three modules—consisting of a cartridge, a central reservoir, and a fast pump, connected by gas-permeable tubing—were assembled within a tissue culture incubator to expose parasites to dynamically changing drug concentrations. The authors bred a strain of P. falciparum that could tolerate usual incubator oxygen concentrations instead of the more conventional in vitro hypoxic environment. They demonstrated the use of their system by assessing two widely used antimalarial drugs: chloroquine and artemisinin. Both drugs are very effective, even though they have quite different kinetics in the body. Chloroquine is retained for weeks before being cleared, whereas artemisinin remains for just a few hours. The authors’ results explain this puzzle: Chloroquine must be present at concentrations above a minimum for an extended time to kill P. falciparum (a TMIC-driven mechanism); in contrast, artemisinin kills when it reaches a certain high concentration (CMAX), even for a brief time.

This apparatus can be used to test candidate antimalarial drugs in the development pipeline, and the results can help to distinguish likely prospects from the less likely. With the need for new drugs so great, any facilitator of the translational process is welcome indeed.

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