Abstract
.Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.
Highlights
An estimated 132–391 million Plasmodium vivax malaria cases occur annually, mostly in India, south and southeast Asia, South America, and the Horn of Africa.[1]
Recruitment of two additional cohorts to receive the maximum tolerated dose was suspended during investigation of a potential genotoxic tafenoquine metabolite identified in urine from this study (100 mg cohort) that triggered an in silico alert, but after investigation with an Ames test, it was found not to be genotoxic in vitro and the study recommenced
The study was concluded at that point as 7/12 planned glucose-6-phosphate dehydrogenase (G6PD)-heterozygous subjects had been recruited and this was felt to be sufficient to evaluate tafenoquine hemolytic potential
Summary
An estimated 132–391 million Plasmodium vivax malaria cases occur annually, mostly in India, south and southeast Asia, South America, and the Horn of Africa.[1] Plasmodium vivax hypnozoites lie dormant in the host liver; their reactivation causing clinical relapses, with substantial health and economic consequences. Primaquine remains efficacious in preventing P. vivax relapse, the 7- to 14-day dosing schedule diminishes treatment effectiveness as poor adherence is associated with clinical failure.[2] In 2012, the World Health Organization collected data on the number of primaquine treatment courses reported by 24 national programs and, based on the estimated number of P. vivax cases in public facilities for each country, concluded that only 10% of P. vivax cases receive primaquine treatment at therapeutic doses.[3] Clearly, there is an unmet need for a therapy that is convenient for patients and appropriate for use in a public health context.[4]
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