Assessing the tolerability of a potentially safer radical curative regimen of primaquine in healthy volunteers with glucose 6 phosphate dehydrogenase

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Malaria, the most important parasite disease of Man, is transmitted by mosquitoes and has two types: Plasmodium falciparum (Pf) and P. vivax (Pv). Outside Africa, where Pf predominates, Pv is the most common malaria species causing an estimated 6-12 million cases and 1800-4900 deaths. Malaria occurs when the parasites enter the red blood cells where they multiply and produce male and female forms that need to be taken up by mosquitoes to complete their life cycle. Pv has found a way to avoid mosquito transmission by developing a sleeping form in the liver, called a hypnozoite which wake up periodically to cause new illnesses, called relapses. In some areas, notably SE Asia, hypnozoites frequently relapse and account for about 80% of all Pv illness.Repeated Pv leads to childhood anaemia, growth retardation, developmental delay, poor school performance, time off work and economic loss. So the hypnozoite reservoir is an important focus of our research. The only available drug to kill hypnozoites is primaquine, a drug developed seventy years ago. Unfortunately, it causes red cell destruction (haemolysis) in people whose red cells are deficient in the enzyme, glucose -6-phosphate dehydrogenase (G6PD). G6PD deficiency (G6PDd) is common and inherited through defective X chromosomes. Thus, in some regions, up to 30% of men have severe G6PDd and some 75% of women have milder G6PDd. G6PDd red cells cannot produce enough antioxidants; the more the red cells are deficient, the fewer antioxidants they produce. When primaquine is metabolised, it produces oxidants that damage red cells resulting in haemolysis. The higher the primaquine dose, the more haemolysis. If severe, patients can become anaemic very quickly which can be life threatening. We can test for G6PDd in the laboratory, which is cumbersome. There are easy to use rapid tests but they are expensive and governments cannot afford to deploy them throughout the health service. So, primaquine is considered dangerous and is not used and this hinders the elimination of Pv. About 60 years ago, doctors found that giving primaquine every week for 8 weeks to African Americans with the mild African form of G6PDd was safe and effective at stopping relapses. However, when this dose was tested in Cambodia, a country with moderately severe G6PDd, some Pv patients had significant falls in haemoglobin (the red pigment in red cells) and one needed to be transfused. Therefore, treated patients should be monitored, another costly precaution. This would apply also in the Middle East, Pakistan and Afghanistan where the most severe G6PDd is present. We asked ourselves this question: "Could primaquine be given more safely to G6PDd patients without requiring G6PD testing ? Primaquine destroys older rather than younger red blood cells. Combining this with knowledge of how red cells are produced, and haemolysis data in healthy individuals and Pv patients given primaquine, we used mathematical modelling to find a primaquine dose that led to a 'slow burn' haemolysis. We found that increasing the dose of primaquine every 5 days for 20 days gave that slow burn haemolysis and the fall in haemoglobin would be less compared to the weekly dose given to the Cambodian patients. The next step is to test this dose in G6PDd males in Thailand where G6PD Mahidol is common and similar to Cambodian G6PD Viangchan. The study is designed so that we can alter the primaquine dose according to the fall in the haemoglobin, called an adaptive design. There will be a tight safety net and all study participants will be monitored closely in hospital and have their haemoglobin checked every day. If this study is successful, we will test the dose in Pv patients and will also adapt the primaquine dose for studies in G6PD Mediterranean countries. Ultimately, if we show that dosing primaquine in steps is safe and effective, it will be a giant leap forward and governments could adopt this new dose quickly.