Safety of 8-aminoquinolines given to people with G6PD deficiency: protocol for systematic review of prospective studies

Uthman, Olalekan A.; Saunders, Rachel; Sinclair, David; Graves, Patricia M.; Gelband, Hellen; Clarke, Aileen; Garner, Paul

doi:10.1136/bmjopen-2013-004664

Cited by 7 publications

(6 citation statements)

References 33 publications

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“…PRISMA checklist is provided in the Additional files 3 . The review protocol was published a priori [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

“…The detection and classification of the genotype and phenotype of G6PD deficiency is complicated and understanding is continually developing (Fig. 1 ; [ 3 ]). An estimated 400 million people worldwide carry G6PD gene mutations [ 4 – 6 ], and the relatively high prevalence of between 5 and 33% in the malaria endemic countries of sub-Saharan Africa and Asia [ 6 ] makes the drug potentially unsafe within these populations.…”

Section: Introductionmentioning

confidence: 99%

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Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies

Uthman

Graves

Saunders

et al. 2017

Malar J

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BackgroundHaemolysis risk with single dose or short course primaquine was evaluated in glucose-6-phosphate dehydrogenase (G6PD) deficient people.MethodsMajor electronic databases (to August 2016) were searched for single or short course 8-aminoquinolines (8-AQ) in (1) randomized comparisons against placebo in G6PD deficient people; and (2) observational comparisons in G6PD deficient compared to replete people. Two authors independently assessed eligibility, risk-of-bias, and extracted data.ResultsFive randomized controlled trials and four controlled observational cohorts were included. In G6PD deficient individuals, high-dose (0.75 mg/kg) PQ resulted in lower average haemoglobin levels at 7 days (mean difference [MD] −1.45 g/dl, 95% CI −2.17 to −0.74, 2 trials) and larger percentage fall from baseline to day 7 (MD −10.31%, 95% CI −17.69 to −2.92, 3 trials) compared to placebo. In G6PD deficient compared to replete people, average haemoglobin was lower at 7 days (MD −1.19 g/dl, 95% CI −1.94 to −0.44, 2 trials) and haemoglobin change from baseline to day 7 was greater (MD −9.10%, 95% CI −12.55 to −5.65, 5 trials). One small trial evaluated mid-range PQ dose (0.4–0.5 mg/kg) in G6PD deficient people, with no difference detected in average haemoglobin at day 7 compared to placebo. In one cohort comparing G6PD deficient and replete people there was a greater fall with G6PD deficiency (MD −4.99%, 95% CI −9.96 to −0.02). For low-dose PQ (0.1–0.25 mg/kg) in G6PD deficient people, haemoglobin change from baseline was similar to the placebo group (MD 1.72%, 95% CI −1.89 to 5.34, 2 trials). Comparing low dose PQ in G6PD deficient with replete people, the average haemoglobin was lower in the G6PD deficient group at 7 days (−0.57 g (95% CI −0.97 to −0.17, 1 trial)); although change from baseline was similar (MD −1.45%, 95% CI −5.69 to 2.78, 3 trials).ConclusionsFalls in average haemoglobin are less marked with the 0.1 to 0.25 mg/kg PQ than with the 0.75 mg/kg dose, and severe haemolytic events are not common. However, data were limited and the evidence GRADE was low or very low certainty.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1989-3) contains supplementary material, which is available to authorized users.

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“…PRISMA checklist is provided in the Additional files 3 . The review protocol was published a priori [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies

Uthman

Graves

Saunders

et al. 2017

Malar J

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“…Since its introduction into the market in the 1950s, primaquine has been documented to trigger haemolysis in individuals with a genetic deficiency in glucose-6-phosphate dehydrogenase (G6PD) [ 3 , 4 ]. Thus, despite the unique therapeutic indications of primaquine, the widespread prevalence of G6PD deficiency across populations in malaria-endemic areas has limited its clinical use [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Enantioselective metabolism of primaquine by human CYP2D6

Fasinu

Tekwani

Nanayakkara

et al. 2014

Malar J

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BackgroundPrimaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers.MethodsStable isotope 13C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites.ResultsThe rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 μM in 120 min) compared to (−)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated Vmax (μmol/min/mg) were 0.75, 0.98 and 0.42, with Km (μM) of 24.2, 33.1 and 21.6 for (±)-primaquine, (+)-primaquine and (−)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH-PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+)-primaquine in a ratio of 4:1 compared to (−)-primaquine. The racemic (±)-primaquine showed a pattern similar to the (−)-primaquine; 2-OH-PQ accounted for about 15–17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (−)-primaquine (5:1), accounting for 22% of the total (−)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (−)-primaquine) was identified and accounted for 18–20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers.ConclusionThe metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers.

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“…In this model, immunodeficient mice are transfused with huRBC from A-or Med-G6PDd huRBC. Treatment with PQ and other 8-AQs known to cause hemolytic toxicity induce a dose-dependent loss of huRBC that is commensurate with the level of G6PD deficiency (5,6). In the present study, we evaluated whether a single dose of PQ given at the HED of 0.25 mpk would induce hemolytic toxicity in either A-or Med-G6PDd huRBC-SCID mice.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its potential for use in malaria transmission-blocking programs (3) and ultimately eradication efforts (4), PQ has been underutilized and distribution has been severely restricted due to the risk of acute hemolytic anemia in populations that have glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) (5,6). G6PD deficiency is the most common human enzymopathy, with an estimated frequency of approximately 3 to 30% in areas where malaria is endemic (7)(8)(9)(10).…”

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confidence: 99%

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs

Wickham

Baresel

Marcsisin

et al. 2016

Antimicrob Agents Chemother

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Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in MedG6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates.

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Safety of 8-aminoquinolines given to people with G6PD deficiency: protocol for systematic review of prospective studies

Cited by 7 publications

References 33 publications

Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies

Safety of primaquine given to people with G6PD deficiency: systematic review of prospective studies

Enantioselective metabolism of primaquine by human CYP2D6

Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs

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