Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial

Mahamar, Almahamoudou; Smit, Merel; Sanogo, Koualy; Sinaba, Youssouf; Niambele, Sidi Mohamed; Sacko, Adama; Kéita, S.; Dicko, Oumar M.; Diallo, Makonon; Maguiraga, Seydina O; Samake, Siaka; Attaher, Oumar; Lanke, Kjerstin; Heine, Rob ter; Bradley, John; McCall, Matthew; Issiaka, Djibrilla; Traorè, Sékou F.; Bousema, Teun; Drakeley, Chris; Dicko, Alassane

doi:10.1016/s2666-5247(21)00356-6

Cited by 13 publications

(26 citation statements)

References 28 publications

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“…In a recent human challenge study, a sustained circulation of mature gametocytes was observed following the treatment of volunteers with piperaquine. That result lays a pathway to a fast and powerful evaluation of the transmission-blocking potential of old or new drugs 64 . For drugs like those identified in here, potentially able to block transmission by inducing splenic gametocyte clearance, the readout for such an evaluation would be the simple measure of gametocytemia following drug administration.…”

Section: Discussionmentioning

confidence: 98%

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

et al. 2023

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Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome (https://clinicaltrials.gov, ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.

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Section: Discussionmentioning

confidence: 98%

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

et al. 2023

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“…The objective of this study was to characterize the blood stage P. falciparum antimalarial activity of tafenoquine in humans, with a view to potentially expanding the utility of the drug beyond its current indications of malaria prophylaxis and radical cure of vivax malaria. The fact that tafenoquine has a very long elimination half-life and exhibits activity against multiple parasite lifecycle stages, including the asexual blood stage [10,11] and gametocytes responsible for transmission [21][22][23], indicated that it may be an appropriate candidate for MDA. The use of medicines with demonstrated efficacy for treatment, at full treatment doses, is important for MDA because some of the individuals treated will be parasitemic.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it seems unlikely that the predicted doses required to clear asexual parasitemia could be safely administered for this purpose in the context of MDA. However, we and others have demonstrated that single low doses of tafenoquine (<100 mg adult dose) can reduce the transmission of P. falciparum to mosquitoes [22, 23]. Thus, the use of tafenoquine for this purpose, in combination with a partner drug to clear asexual parasitaemia, may be worthy of investigation for MDA.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected withPlasmodium falciparum

Barber

Abd-Rahman

Webster

et al. 2022

Preprint

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Background The long acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. Methods Healthy G6PD-normal adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia, and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48+/-2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n=3), 300 mg (n=4), 400 mg (n=2), or 600 mg (n=3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 h and 4.2 h respectively) was faster than with 200 mg or 300 mg (11.8 h and 9.6 h respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants), but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 10^6 and 10^9, respectively, in a 60 kg adult. Conclusions Although a single dose or tafenoquine exhibits potent P. falciparum blood stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency.

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“…Additionally, a study in Afghanistan has demonstrates that G6PD deficiency protects against P. vivax clinical disease [ 6 ]. Even though G6PD deficiency provides clinical protection against Plasmodium spp., G6PD-deficient patients are susceptible to haemolytic anaemia when exposed to active and toxic metabolites of primaquine (PQ) and tafenoquine (TQ) [ 7 – 9 ]. PQ and TQ are anti-malarial drugs that reduce Plasmodium falciparum gametocytes for transmission and preventing the relapse of P. vivax and Plasmodium ovale malaria [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Even though G6PD deficiency provides clinical protection against Plasmodium spp., G6PD-deficient patients are susceptible to haemolytic anaemia when exposed to active and toxic metabolites of primaquine (PQ) and tafenoquine (TQ) [ 7 – 9 ]. PQ and TQ are anti-malarial drugs that reduce Plasmodium falciparum gametocytes for transmission and preventing the relapse of P. vivax and Plasmodium ovale malaria [ 8 , 9 ]. In 2013, Howes et al published the spatial distribution of G6PD deficiency and its mutations in malaria-endemic areas around the globe to support the safe use of PQ and TQ [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Haematological profile of malaria patients with G6PD and PKLR variants (erythrocytic enzymopathies): a cross-sectional study in Thailand

Mungkalasut

Kiatamornrak

Jugnam-Ang

et al. 2022

Malar J

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Background Glucose 6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PKLR) deficiencies are common causes of erythrocyte haemolysis in the presence of antimalarial drugs such as primaquine and tafenoquine. The present study aimed to elucidate such an association by thoroughly investigating the haematological indices in malaria patients with G6PD and PKLRR41Q variants. Methods Blood samples from 255 malaria patients from Thailand, Myanmar, Laos, and Cambodia were collected to determine haematological profile, G6PD enzyme activity and G6PD deficiency variants. The multivariate analysis was performed to investigate the association between anaemia and G6PD MahidolG487A, the most common mutation in this study. Results The prevalence of G6PD deficiency was 11.1% (27/244) in males and 9.1% (1/11) in female. The MAFs of the G6PD MahidolG487A and PKLRR41Q variants were 7.1% and 2.6%, respectively. Compared with patients with wildtype G6PD after controlling for haemoglobinopathies, G6PD-deficient patients with hemizygous and homozygous G6PD MahidolG487A exhibited anaemia with low levels of haemoglobin (11.16 ± 2.65 g/dl, p = 0.041). These patients also exhibited high levels of reticulocytes (3.60%). The median value of G6PD activity before treatment (Day 0) was significantly lower than that of after treatment (Day 28) (5.51 ± 2.54 U/g Hb vs. 6.68 ± 2.45 U/g Hb; p < 0.001). Reticulocyte levels on Day 28 were significantly increased compared to that of on Day 0 (2.14 ± 0.92% vs 1.57 ± 1.06%; p < 0.001). PKLRR41Q had no correlation with anaemia in malaria patients. The risk of anaemia inpatients with G6PDMahidolG487A was higher than wildtype patients (OR = 3.48, CI% 1.24–9.75, p = 0.018). Univariate and multivariate analyses confirmed that G6PDMahidolG487A independently associated with anaemia (< 11 g/dl) after adjusted by age, gender, Plasmodium species, parasite density, PKLRR41Q, and haemoglobinopathies (p < 0.001). Conclusions This study revealed that malaria patients with G6PD MahidolG487A, but not with PKLRR41Q, had anaemia during infection. As a compensatory response to haemolytic anaemia after malaria infection, these patients generated more reticulocytes. The findings emphasize the effect of host genetic background on haemolytic anaemia and the importance of screening patients for erythrocyte enzymopathies and related mutations prior to anti-malarial therapy.

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Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial

Cited by 13 publications

References 28 publications

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening

Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected withPlasmodium falciparum

Haematological profile of malaria patients with G6PD and PKLR variants (erythrocytic enzymopathies): a cross-sectional study in Thailand

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