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
Background:
Biological aging exhibits heterogeneity across multi-organ systems. However, it remains unclear how is lifestyle associated with overall and organ-specific aging and which factors contribute most in Southwest China.
Methods:
This study involved 8396 participants who completed two surveys from the China Multi-Ethnic Cohort (CMEC) study. The healthy lifestyle index (HLI) was developed using five lifestyle factors: smoking, alcohol, diet, exercise, and sleep. The comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera–Doubal method based on longitudinal clinical laboratory measurements, and validation were conducted to select BA reflecting related diseases. Fixed effects model was used to examine the associations between HLI or its components and the acceleration of validated BAs. We further evaluated the relative contribution of lifestyle components to comprehension and organ systems BAs using quantile G-computation.
Results:
About two-thirds of participants changed HLI scores between surveys. After validation, three organ-specific BAs (the cardiopulmonary, metabolic, and liver BAs) were identified as reflective of specific diseases and included in further analyses with the comprehensive BA. The health alterations in HLI showed a protective association with the acceleration of all BAs, with a mean shift of –0.19 (95% CI −0.34, –0.03) in the comprehensive BA acceleration. Diet and smoking were the major contributors to overall negative associations of five lifestyle factors, with the comprehensive BA and metabolic BA accounting for 24% and 55% respectively.
Conclusions:
Healthy lifestyle changes were inversely related to comprehensive and organ-specific biological aging in Southwest China, with diet and smoking contributing most to comprehensive and metabolic BA separately. Our findings highlight the potential of lifestyle interventions to decelerate aging and identify intervention targets to limit organ-specific aging in less-developed regions.
Funding:
This work was primarily supported by the National Natural Science Foundation of China (Grant No. 82273740) and Sichuan Science and Technology Program (Natural Science Foundation of Sichuan Province, Grant No. 2024NSFSC0552). The CMEC study was funded by the National Key Research and Development Program of China (Grant No. 2017YFC0907305, 2017YFC0907300). The sponsors had no role in the design, analysis, interpretation, or writing of this article.
