Rationale for recommending a lower dose of primaquine as a Plasmodium falciparum gametocytocide in populations where G6PD deficiency is common

Abstract

In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated.

Figure 1

The rapid sterilizing effect of primaquine in falciparum malaria; studies of mosquito infectivity following anti-malarial treatments of falciparum malaria with plasmoquine or primaquine in which oocyst assessments were made in mosquitoes which fed 24 hours after drug administration. Oocysts were assessed typically in 10–20 mosquitoes 6–7 days after feeding Medians (IQR) and ranges shown. Gametocytaemia changed little in 24 hours (although it usually fell rapidly thereafter) (left side) (N=51), whereas oocyst numbers fell rapidly and were not found at all in the majority of mosquito batches fed on treated patients (right side) (N=79). When the fed mosquitoes were evaluated later sporozoites were correspondingly absent) [15].

Figure 2

Dose–response relationships for primaquine in reducing the infectivity of P. falciparum infected subjects to anopheline mosquitoes. Vertical axis shows the proportion of fed anopheline mosquitoes which were infected. Pooled data from all studies conducted [15,28]. Left: Oocyst formation (proportion of patients who were still infectious to mosquitoes) from blood sampled 24 hours after primaquine dose, Right : Oocyst formation from blood sampled 48 hours after primaquine dose. Primaquine given with an artemisinin derivative is shown in green, and with a non-artemisinin derivative or no anti-malarial is shown in red. In these studies 29 patients received no primaquine. The size of the circle is proportional to the number of subjects in each group (shown within).

Figure 3

Dose–response relationships for primaquine in reducing infectivity to anopheline mosquitoes as in Figure2, assessing sporozoite formation. Left: Sporozoite formation assessed from blood sampled 24 hours after primaquine dose, Right: Sporozoite formation assessed from blood sampled 48 hours after primaquine dose. Numbers are not exactly the same as in Figure  2 because sporozoites were not assessed in all studies.

Figure 4

Studies of ⁵¹Cr labelled red cell survival in healthy adult hemizygous male volunteers with the A-variant of G6PD deficiency exposed to different dose regimens of primaquine in studies conducted by the University of Chicago-Army Medical Research Unit at the Illinois State penitentiary (Stateville) from 1950 to 1962. Daily doses are shown within the range of red cell survivals that resulted. Daily administration of 45 mg base primaquine was considered to result in “dangerous haemolytic anaemia”, daily administration of 30 mg resulted in severe haemolysis and acute anaemia, and daily administration of 15 mg resulted in moderate haemolysis and mild anaemia [36].

Figure 5

Once weekly administration of primaquine 45 mg base for 8 weeks to healthy adult hemizygous male volunteers with the A- variant of G6PD deficiency resulted in less anaemia than daily administration of 15 mg for two weeks[35].

Figure 6

Global distribution of polymorphic G6PD deficiency mutants[47].