Short report: a consideration of primaquine dose adjustment for radical cure of Plasmodium vivax malaria.

Abstract

Abstract. Relapse of Plasmodium vivax malaria following standard primaquine dosing has been reported from many areas, and more recently from sub-Saharan Africa. In this report we describe eight episodes (in five patients) of treatment failure in non-immune Israeli travelers returning from Ethiopia. Retrospective calculation of the primaquine dose per kilogram of body weight for 23 treatment courses showed a lower total dose per kilogram in heavier patients. The mean calculated dose (95% CI) in the eight failed treatments was 2.5 Ϯ 0.3 mg/kg compared with 4.4 Ϯ 0.5 mg/kg in the 15 successful treatment courses. Weight-adjusted dosing regimens may prevent inadvertent subtherapeutic drug failure, and thus apparent primaquine failure. In these cases, no relapses were observed in those who received Ͼ 3.5 mg/kg. Consideration should be given to adjusting the dose of primaquine according to body weight. For those infected by strains from Ethiopia a dose Ͼ 3.5 mg/kg is preferable.Although Plasmodium vivax accounts for less than 10% of the malaria cases in Africa, there has been an increase in recent accounts of infection among travelers to these regions, such as Israelis returning from Ethiopia 1 and U.S. military returning from Somalia. 2

Primaquine revisited six decades after its discovery

“…These dimers of N-acetylprimaquine were inactive in vitro as anti-malarials, thus reinforcing the idea that the free primary amino group on the aliphatic chain of PQ is essential for anti-malarial activity [156,157]. Peroxodisulfate oxidation of PQ has also been shown to produce dimeric derivatives of the unacetylated drug (22,23), both of which were active as schizontocides [158]. Moreover, compound 22 was found to have a gametocytocidal activity superior to that of PQ, whereas compound 23 was significantly less active [158].…”

Primaquine Dosing Errors: The Human Cost of a Pharmaceutical Anachronism

“…Fixed dose regimens may fail to protect large and overweight travelers. 12 Even with the correct dose, a few patients (also seen in our series) still develop malaria. In this respect, it is important to note that people with poor or intermediate activity of cytochrome P450 2D6 (~17% Israeli adults 13 ) may not adequately metabolize primaquine to its active metabolite and thus become infected with malaria.…”

Prevention and treatment of vivax malaria

“…Thus, the recommendation for the 15 mg/day regimen has been re-evaluated and altered [24•,37]. Most experts would now recommend 0.5 mg/kg/day for 14 days with a maximum dose of 30 mg/day for Oceania and Southeast Asia, and lower doses in parts of the world such as Ethiopia [51]. For heavy patients (> 80 kg) in Oceania and Southeast Asia, we recommend administering 30 mg daily to achieve a total dose of 6 mg/kg over as many days as is required [24•].…”