Abstract
BackgroundAs anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. The US Army is developing tafenoquine (TQ), an analogue of primaquine (PQ), which is expected to be more effective in preventing malaria in deployed military personnel.MethodsTo compare the prophylactic efficacy of TQ and PQ, a transgenic Plasmodium berghei parasite expressing the bioluminescent reporter protein luciferase was utilized to visualize and quantify parasite development in C57BL/6 albino mice treated with PQ and TQ in single or multiple regimens using a real-time in vivo imaging system (IVIS). As an additional endpoint, blood stage parasitaemia was monitored by flow cytometry. Comparative pharmacokinetic (PK) and liver distribution studies of oral and intravenous PQ and TQ were also performed.ResultsMice treated orally with three doses of TQ at 5 mg/kg three doses of PQ at 25 mg/kg demonstrated no bioluminescence liver signal and no blood stage parasitaemia was observed suggesting both drugs showed 100% causal activity at the doses tested. Single dose oral treatment with 5 mg TQ or 25 mg of PQ, however, yielded different results as only TQ treatment resulted in causal prophylaxis in P. berghei sporozoite-infected mice. TQ is highly effective for causal prophylaxis in mice at a minimal curative single oral dose of 5 mg/kg, which is a five-fold improvement in potency versus PQ. PK studies of the two drugs administered orally to mice showed that the absolute bioavailability of oral TQ was 3.5-fold higher than PQ, and the AUC of oral TQ was 94-fold higher than oral PQ. The elimination half-life of oral TQ in mice was 28 times longer than PQ, and the liver tissue distribution of TQ revealed an AUC that was 188-fold higher than PQ.ConclusionsThe increased drug exposure levels and longer exposure time of oral TQ in the plasma and livers of mice highlight the lead quality attributes that explain the much improved efficacy of TQ when compared to PQ.
Highlights
As anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections
In the untreated control animals, there was a strong increase in bioluminescence signal at 48 hours, and the liver region of intensity (ROI) was increased 17.2-fold when compared to 24 hours subjects
The liver stage of P. berghei is 48 hours in duration, and no significant blood stage activity was not observed after the 48 hour liver stage was completed (Figure 2, right)
Summary
As anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. The 8-aminoquinoline (8-AQ) anti-malarials, such as primaquine (PQ), have attracted much interest as chemotherapeutic and prophylactic agents against the liver stages of Plasmodium vivax and Plasmodium falciparum malaria parasites (Figure 1). The 8-AQs are the only known class of drugs with activity against both P. vivax hypnozoites and P. falciparum gametocytes. TQ has advantages as a chemoprophylactic agent, which is needed to address the problems of patient drug compliance, tolerance, and efficacy in both semi-immune and nonimmune populations [4]. Phase I, II, and III clinical studies have shown that TQ is a safe, well-tolerated, and highly effective oral chemoprophylactic agent for the treatment of Plasmodium infections [5,6,7]
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