Improving safety for antimalarial drugs

New concept helps identify patients at risk of adverse effects if treated with some antimalarials

31 Aug 2012

Primaquine is the only medicine approved for the radical cure of relapsing Plasmodium vivax malaria. However, the drug can lead to hemolytic anemia in recipients who are deficient in an enzyme, glucose 6-phosphate dehydrogenase (G6PD). Genetic deficiency in G6PD occurs in over 400 million people, most of whom are located in malaria-endemic regions.

MMV and GSK are partners in the development of tafenoquine, for the radical cure of P vivax. Tafenoquine should improve patient compliance compared with primaquine, because a shorter course of treatment is required. As tafenoquine can also induce hemolytic anemia in G6PD-deficient patients, a test is needed to identify patients who are at risk, before either drug can be safely administered. Accordingly, MMV and GSK are working with several organisations towards developing a rapid diagnostic test (RDT) for G6PD-deficiency, that should be affordable, requires little infrastructure and is suitable for use by staff with minimal training in remote tropical areas.

There are several challenges in developing a suitable RDT, including the need to obtain a stable read-out and the variation of apparent G6PD activity according to ambient temperature. The first difficulty arises because G6PD-deficient samples continue to generate product after a normal sample has exhausted all of its substrate. So a deficient sample may not give a stable “deficient” reading, but instead proceed to produce a false “normal” reading. Another difficulty arises because, like other enzymes, the activity of G6PD increases with temperature.  Performing a test a few degrees above the temperature used to calibrate the RDT can cause a sample with moderate G6PD-deficiency to exhibit a false “normal” level of activity. Conversely, if the temperature is too low, then samples with normal G6PD activity can appear deficient, so that access to the medicine could be denied to people who are actually safe to benefit.

Tim Wells, CSO of MMV has suggested a potential solution for these two problems. His concept is to include in the test, an enzyme, which competes for one or more of the G6PD substrates (see above figure). Thus, a G6PD-deficient sample could not generate a false “normal” signal because the substrate would be consumed by the competing enzyme. The test would be run until the reaction stops, due to exhaustion of one or more substrates. There is no further generation of product, resulting in a stable read-out. The competing enzyme and G6PD have similar dependence upon temperature, so that changing the temperature no longer would give a misleading result.

A similar “competing enzyme RDT” could be useful to support treatment with other drugs, which cause liver damage, releasing marker enzymes into the blood. The MMV/GSK G6PD team has discussed this competing enzyme concept with several organisations who are interested in the development of an RDT to support the use of primaquine and tafenoquine.