The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: an individual patient data meta-analysis
- Oxford University Clinical Research Unit, Viet Nam
- Charles Darwin University, Australia
- Mahidol University, Thailand
- University of Melbourne, Australia
- Universidad Peruana Cayetano Heredia, Peru
- Tropical Medicine Foundation, Brazil
- GlaxoSmithKline, United Kingdom
- Northwick Park Hospital, United Kingdom
Abstract
Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled individual data from 1,102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300mg dose in a 60kg adult (5mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5mg/kg (i.e. 450mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine's hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.
Data availability
The data used in this study can be accessed by submitting a research proposal via www.ClinicalStudyDataRequest.com using the following study codes: GSK-TAF112582; GSK-200951; GSK-TAF116564. Decisions to share data with independent researchers is made via an Independent Review Panel. All code used to process the data is available on https://github.com/jwatowatson/Tafenoquine-efficacy
Article and author information
Author details
Funding
Wellcome Trust (223253/Z/21/Z)
- James A Watson
Wellcome Trust (093956/Z/10/C)
- Nicholas J White
Australian NHMRC (1194702)
- Robert J Commons
Wellcome Trust (200909)
- Richard N Price
Australian NHMRC (1196068)
- Julie A Simpson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Anonymised individual patient data were obtained via ClinicalStudyDataRequest.com following approval of a research proposal from the Independent Review Panel.Re-use of existing, appropriately anonymised, human data does not require ethical approval under the Oxford Tropical Research Ethics Committee regulations (OxTREC).
Copyright
© 2022, Watson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: an individual patient data meta-analysis
eLife 11:e83433.
https://doi.org/10.7554/eLife.83433
Further reading
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Several areas of the world suffer a notably high incidence of Shiga toxin-producing Escherichia coli. To assess the impact of persistent cross-species transmission systems on the epidemiology of E. coli O157:H7 in Alberta, Canada, we sequenced and assembled E. coli O157:H7 isolates originating from collocated cattle and human populations, 2007–2015. We constructed a timed phylogeny using BEAST2 using a structured coalescent model. We then extended the tree with human isolates through 2019 to assess the long-term disease impact of locally persistent lineages. During 2007–2015, we estimated that 88.5% of human lineages arose from cattle lineages. We identified 11 persistent lineages local to Alberta, which were associated with 38.0% (95% CI 29.3%, 47.3%) of human isolates. During the later period, six locally persistent lineages continued to be associated with human illness, including 74.7% (95% CI 68.3%, 80.3%) of reported cases in 2018 and 2019. Our study identified multiple locally evolving lineages transmitted between cattle and humans persistently associated with E. coli O157:H7 illnesses for up to 13 y. Locally persistent lineages may be a principal cause of the high incidence of E. coli O157:H7 in locations such as Alberta and provide opportunities for focused control efforts.
