Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial

Chen, Ingrid; Diawara, Halimatou; Mahamar, Almahamoudou; Sanogo, Koualy; Kéita, S.; Kone, D; Diarra, Kalifa; Djimdé, Moussa; Kéïta, Mohamed; Brown, Joelle; Roh, Michelle E.; Hwang, Jimee; Pett, Helmi; Murphy, Maxwell; Niemi, Mikko; Greenhouse, Bryan; Bousema, Teun; Gosling, Roly; Dicko, Alassane

doi:10.1093/infdis/jiy014

Cited by 19 publications

(19 citation statements)

References 20 publications

(19 reference statements)

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“…For single low-dose primaquine, doses from 0·25 mg/kg 30 to 0·40 mg/kg have been shown to be safe among G6PD-deficient individuals aged 5–50 years. 31 …”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

Dicko¹,

Roh

Diawara³

et al. 2018

The Lancet Infectious Diseases

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122

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SummaryBackgroundPrimaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants.MethodsThis was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023.FindingsBetween June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild).InterpretationAdding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly effi...

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“…For single low-dose primaquine, doses from 0·25 mg/kg 30 to 0·40 mg/kg have been shown to be safe among G6PD-deficient individuals aged 5–50 years. 31 …”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

Dicko¹,

Roh

Diawara³

et al. 2018

The Lancet Infectious Diseases

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122

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“…Most studies evaluating the safety of PQ intake in G6PDd patients are based on P. falciparum infections receiving a single dose of PQ administered at different concentrations (0.25 or 0.4 mg/kg [ 34 , 35 ]; 0.4–0.5 mg/kg [ 36 ]; 0.1, 0.4, 0.75 mg/kg [ 37 ]; 0.7 mg/kg [ 38 ]). Those studies seem to agree on two points: that the adverse effects of PQ at low doses are usually mild or moderate even in patients with G6PDd; and that safety depends primarily on primaquine doses, as well as the variant of G6PD deficiency.…”

Section: Discussionmentioning

confidence: 99%

G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients

Ávalos

Mejía²,

Banegas³

et al. 2018

Malar J

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BackgroundThe incidence of malaria in the Americas has decreased markedly in recent years. Honduras and the other countries of Mesoamerica and the island of Hispaniola have set the goal of eliminating native malaria by the year 2020. To achieve this goal, Honduras has recently approved national regulations to expand the possibilities of a shortened double dose primaquine (PQ) treatment for vivax malaria. Considering this new shortened anti-malarial treatment, the high frequency of G6PDd genotypes in Honduras, and the lack of routinely assessment of the G6PD deficiency status, this study aimed at investigating the potential association between the intake of PQ and haemolysis in malaria-infected G6PDd subjects.MethodsThis was a prospective cohort and open-label study. Participants with malaria were recruited. Plasmodium vivax infection was treated with 0.25 mg/kg of PQ daily for 14 days. Safety and signs of haemolysis were evaluated by clinical criteria and laboratory values before and during the 3rd and 7th day of PQ treatment. G6PD status was assessed by a rapid test (CareStart™) and two molecular approaches.ResultsOverall 55 participants were enrolled. The frequency of G6PD deficient genotypes was 7/55 (12.7%), where 5/7 (71.4%) were hemizygous A− males and 2/7 (28.6%) heterozygous A− females. Haemoglobin concentrations were compared between G6PD wild type (B) and G6PDd A− subjects, showing a significant difference between the means of both groups in the 3rd and 7th days. Furthermore, a statistically significant difference was evident in the change in haemoglobin concentration between the 3rd day and the 1st day for both genotypes, but there was no statistical difference for the change in haemoglobin concentration between the 7th day and the 1st day. Besides these changes in the haemoglobin concentrations, none of the patients showed signs or symptoms associated with severe haemolysis, and none needed to be admitted to a hospital for further medical attention.ConclusionsThe findings support that the intake of PQ during 14 days of treatment against vivax malaria is safe in patients with a class III variant of G6PDd. In view of the new national regulations in the shortened treatment of vivax malaria for 7 days, it is advisable to be alert of potential cases of severe haemolysis that could occur among G6PD deficient hemizygous males with a class II mutation such as the Santamaria variant, previously reported in the country.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2564-2) contains supplementary material, which is available to authorized users.

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“…Gametocyte detection was performed following treatment with a single dose of 0.1 to 0.75 mg/kg PQ in combination with either artemether-lumefantrine (AL) (Coartem as a standard 6-dose regimen over 3 days; Novartis Pharma, Switzerland) in Burkina Faso (3) and Uganda (2) or dihydroartemisinin-piperaquine (DP) (Eurartesim as a standard 3-day regimen; Sigma-Tau, Italy) in Mali (1), the Gambia (4), and Kenya (5). Analyses on the impact of CYP2D6 inferred metabolizer status on hemolysis were restricted to G6PD-deficient (G6PDd) individuals; we included two additional studies that specifically assessed PQ safety in G6PD-deficient individuals in Mali (20) and the Gambia (19), using 0.25 to 0.5 mg/kg PQ in combination with DP. In all studies, hemoglobin (Hb) concentrations in grams per deciliter were measured by a self-calibrating HemoCue photometer (Ängelholm, Sweden).…”

Section: Methodsmentioning

confidence: 99%

“…G6PD is an enzyme involved in the pentose phosphate pathway in human red blood cells (18), and G6PD deficiency (G6PDd) is associated with hemolysis following treatment with PQ. Despite safety concerns related to the hemolytic activity of PQ in individuals with G6PDd, a single low dose of PQ is considered safe in individuals with the most common African G6PDd variant (G6PDd A variant) (19–21). Since genetic variation in CYP2D6 influences the pharmacokinetics of single-low-dose PQ in humans (22), this variation may have implications for PQ efficacy or safety at doses targeting P.…”

Section: Introductionmentioning

confidence: 99%

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

Pett

Bradley

Okebe

et al. 2019

Antimicrob Agents Chemother

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Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.

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Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial

Cited by 19 publications

References 20 publications

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial

G6PD deficiency, primaquine treatment, and risk of haemolysis in malaria-infected patients

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum

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