Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'

  1. James A Watson  Is a corresponding author
  2. Robert J Commons
  3. Joel Tarning
  4. Julie A Simpson
  5. Alejandro Llanos Cuentas
  6. Marcus VG Lacerda
  7. Justin A Green
  8. Gavin CKW Koh
  9. Cindy S Chu
  10. François H Nosten
  11. Richard N Price
  12. Nicholas PJ Day
  13. Nicholas J White  Is a corresponding author
  1. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Viet Nam
  2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom
  3. WorldWide Antimalarial Resistance Network, United Kingdom
  4. Global Health Division, Menzies School of Health Research, Charles Darwin University, Australia
  5. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand
  6. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Australia
  7. Unit of Leishmaniasis and Malaria, Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia, Peru
  8. Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Brazil
  9. GSK, United Kingdom
  10. Department of Infectious Diseases, Northwick Park Hospital, United Kingdom
  11. Shoklo Malaria Research Unit, Thailand

Abstract

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.

Introduction

Most antimalarial drugs have required dose optimisation following their initial introduction. It appears likely that tafenoquine is not an exception. The optimal doses of the 8-aminoquinoline drugs (primaquine and tafenoquine) in the prevention of Plasmodium vivax relapse are a trade-off between the blood stage and hypnozoite effects (benefiting all patients), and the haemolytic risk in the sub-group of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The dose-response relationship for tafenoquine-induced haemolysis in G6PD deficiency has not been well characterised (the entirety of the available data for the 300 mg dose comprises 3 heterozygous females with >40% enzyme activity, Rueangweerayut et al., 2017) but the risk is regarded as substantial, which is why the drug is restricted to patients with G6PD activity >70%. Compared with primaquine, the most widely used 8-aminoquinoline antimalarial, tafenoquine, if not used appropriately, may have a higher risk of causing severe haemolysis. Primaquine can be stopped once haemolysis is apparent, and the effect is short-lived. Tafenoquine has an elimination half-life of approximately 16 days and cannot be “stopped”. As high doses (up to 15 mg/kg) of tafenoquine are well tolerated in G6PD normal individuals (the substantial majority of patients, Watson et al., 2022), and prevention of relapse provides substantial health benefits (Dini et al., 2020), our individual patient data meta-analysis focused on efficacy. We concluded that the current dose has sub-optimal efficacy, and recommended evaluation of higher doses.

Sharma et al challenge our findings. They “assert that, collectively, these data confirm that the benefit–risk profile of a single 300 mg dose of tafenoquine [...] continues to be favourable” (Sharma et al., 2024). We believe that this opinion is not supported by the facts. There is no need to wait for ‘real-world evidence’ to confirm superior efficacy of higher tafenoquine doses when the available clinical trial data demonstrate this relationship beyond reasonable doubt. Instead, randomised clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.

The following provides a point-by-point reply to Sharma et al.

Sharma et al. state that in the DETECTIVE study ‘doubling the tafenoquine dose from 300 mg to 600 mg was associated with only a marginal increase (from 89.2% to 91.9%) in the primary efficacy endpoint’.

The DETECTIVE phase 2 trial was small. Only 57 patients received 300 mg and 56 received 600 mg, distributed across four different countries. One of the countries was India where long latency relapse strains are found. These relapses would have occurred after 6 months (the study’s follow up duration). There was substantial variation in body weight. Direct comparison between the two doses ignores body weight variation (i.e. the major determinant of efficacy) and is underpowered. We fit a logistic regression model to the DETECTIVE phase 2 efficacy data. We estimate an odds ratio for any recurrence at 6 months of 0.67 per mg/kg increase (95% CI 0.58–0.76). At 4 months this odds ratio is 0.62 (95% CI 0.51–0.72), i.e. almost identical to our results from the pooled dataset (Watson et al., 2022).

Sharma et al. ask what we mean by ‘optimal primaquine regimens’, and whether these are ‘WHO-recommended schedules of primaquine or regimens defined as optimal based on nonregulatory studies of primaquine’. We note that there have been no regulatory studies of primaquine. A primaquine total dose of 7 mg/kg is approved by WHO for the Southeast Asian region. A pooled individual patient data meta-analysis shows that this dose is clearly more efficacious than 3.5 mg/kg (Commons et al., 2023).

Results

Efficacy models employed by Watson et al

Sharma et al. state that ‘Details of how the best predictor was selected and how statistical significance was judged were not provided’. The code for the statistical analysis is openly accessible. For the main analysis it is provided as an RMarkdown file (GitHub, copy archived at Watson, 2023). As expected, the plasma tafenoquine AUC and Cmax values are highly correlated with the mg/kg dose, whereas the terminal elimination half-life is not. For the AUC and the Cmax, we compared results for analyses which did and did not adjust for the mg/kg dose. When adjusting for the mg/kg dose, there was no longer a clear relationship between AUC and the odds of recurrence (95% CI for the adjusted odds ratio is 0.64–1.23), or the Cmax and recurrence (95% CI for the adjusted odds ratio is 0.69–1.49). The corresponding code can be found on lines 981 and after (section ‘AUC’), and lines 1023 and after (section ‘CMAX’) in the main RMarkdown file.

Use of a 4-month versus 6-month follow-up period

The optimal duration of follow-up in a study of radical curative efficacy remains debated. In most tropical regions P. vivax relapses are highly predictable and occur within a few weeks to months after initial treatment. Trials which have included no 8-aminoquinoline treatment arms indicate that >90% of first relapses occur within four months (Commons et al., 2023). Longer follow-up increases sensitivity (more relapses included) but lowers specificity (more reinfections included). The results of our analysis are almost identical when a 6 month endpoint was applied. This was shown in Appendix 1—figures 4 and 5 in Watson et al., 2022.

Sharma et al. consider that we provide insufficient detail of the sensitivity analysis which included patients receiving 300 mg only. The sensitivity analysis is given on line 501 in the section “Logistic Regression” in the main RMarkdown (TQ_efficacy.Rmd). The exact same analysis as the primary analysis was performed on the restricted subset of patients who received a 300 mg dose of tafenoquine.

Sharma et al. ask how the dosing bands were chosen for our Figure 2. The selected bands were chosen for simplicity of visualisation ensuring enough patients fell into each category and were thus meaningful. Importantly, no quantitative results depend upon this categorisation.

Rationale for tafenoquine dose selection

Sharma et al. state that we did not discuss ‘the classification and regression tree analysis, in which a clinically relevant breakpoint tafenoquine AUC value of 56.4 µg·h/mL was identified’.

The relevance of the quoted 56.4 µg.h/ml threshold for AUC is unclear. We do not see why this threshold as determined should be considered “clinically relevant”. A CART model determines optimal breakpoints by minimising a given loss function. It appears from the cited publication (Tenero et al., 2015) that the authors used the default parameters in the rpart function in R (from the rpart package). If this is correct, then it would imply that the CART model was fit using the Gini criterion, thus maximising the ‘purity’ of the split (recurrence vs no recurrence). The Gini criterion is not an appropriate choice. Under the Gini criterion the cut-off threshold is the value which equally balances sensitivity and specificity for a continuous covariate which has a continuous relationship with the outcome (e.g. a linear relationship on the log-odds scale). Box 1 gives a hypothetical example (where X is analogous to weight) whereby the Gini criterion selects as optimal the value for which the probability of recurrence is exactly 0.5. We do not believe that this should be considered optimal.

Box 1

Why a CART model using the Gini criterion is an inappropriate choice for the estimation of the optimal tafenoquine dose.

Suppose XNormal(0,1) and YBernoulli(p) where p=ex/(1+ex). Then, for large positive value of x, E[y|x]1 and for large negative value of x, E[y|x]0. Given a large sample realisation of the random variables X and Y under this data generating process, the optimal split for the Gini criterion would be x=0 (Figure 1). If y=1 was ‘no recurrence’ and y=0 ‘recurrence’, it is unclear why the optimal value of a determinant x should be the value for which the probability of recurrence is 0.5. ‘Clinical relevance’ implies a value proposition, whereby a utility (or loss) is assigned to each outcome. In terms of efficacy and tolerability only, an optimal dose would be in an area where the dose-response is flat (i.e where increases in the dose lead to very marginal increases in efficacy), not where it is the steepest.

Hypothetical example showing why the Gini criterion does not lead to a split which is clinically relevant in this context.

Under this data generating process, the optimal split for the Gini criterion is at x=0, corresponding to a probability of 0.5 that y=1.

Sharma et al. quote the TEACH study (paediatric tafenoquine study) as validation of the AUC approach to tafenoquine dose selection (Vélez et al., 2022). Firstly, we note that TEACH was a single arm, non-randomised study with no control group. Hence “efficacy” (a causal concept) is ill-defined. Secondly, we note that the mg/kg doses in TEACH were higher on average than in the adult efficacy studies. Using the reported mean body weights (Table 1 in Vélez et al., 2022), the mean dose was approximately 7.0 mg/kg.

Sharma et al. state that in the INSPECTOR study (Sutanto et al., 2023), body weight was not a significant predictor of efficacy. Firstly, no coefficient values or confidence intervals were provided in the cited publication and a p-value >0.05 does not prove the null hypothesis. Secondly, the tabular results presented in the paper suggest that the efficacy of tafenoquine was greater in the lighter patients. The failure rate was 67% in the patients weighing ≤69kg, but was 91% in the patients weighing >69 kg (odds ratio for failure is 5.3 [95%CI 1.0–27.5; P=0.07]).

Use of an ‘unvalidated’ biomarker

Sharma et al. dispute our causal model for tafenoquine because ‘Central to this model are methaemoglobin (MetHb) production and active metabolites’. They regard methaemoglobin as problematic because it is considered an ‘unvalidated biomarker of tafenoquine efficacy’.

The observation that tafenoquine and primaquine cause increases in blood methaemoglobin is uncontroversial. A recent analysis of different 8-aminoquinoline studies conducted over the past 80 years shows a clear relationship between radical curative efficacy and methaemoglobinaemia (White et al., 2022). There is also general agreement that the gametocytocidal and hypnozoitocidal activities of tafenoquine’s predecessor primaquine result from the generation of reactive intermediates. The contentious part of the causal diagram in our paper is presumably that we consider tafenoquine to be similar, i.e. that the increase in methaemoglobin following tafenoquine is caused by its metabolites rather than the parent compound. Tafenoquine clinical trial data show that greater methaemoglobin values on day 7 are correlated with a lower probability of recurrence at 4 months (after adjustment for the mg/kg dose, Watson et al., 2022). This is the same relationship observed for primaquine and pamaquine (plasmoquine), suggesting these structurally related compounds all share a common mode of action. Importantly this hypothesis was prespecified before the tafenoquine meta-analysis (White et al., 2022). We believe that pre-registering the hypothesis that methaemoglobin is a biomarker of efficacy and then demonstrating an association in a large dataset provides strong evidence to support it as a biomarker.

Sharma et al. state: ‘increases in blood MetHb concentrations after tafenoquine administration were highly correlated with mg/kg dose, but no correlation coefficients, indicating strength of correlation, were discussed in the manuscript’. Based on the responses to our first draft, there appears to be a mis-understanding of the word ‘correlation’. Correlation denotes an association between two variables, not restricted to a causal relationship. Correlation can be quantified in a variety of ways, not limited to covariance (defined as the expectation of the product of two random variables). We quantified the correlation between the tafenoquine mg/kg dose and the day 7 methaemoglobin using the linear model coefficient: ‘Each additional mg/kg was associated with a 19% (95% CI: 17% to 21%) increase in day 7 MetHb concentrations’. The strength of the correlation is also made clear from Figure 3c.

Potential safety concerns

The safety concern for tafenoquine is largely confined to patients with G6PD deficiency. There are two discrete sequential risk distributions for these G6PD deficient patients, neither of which have been well characterised. First, there is the probability of errors with quantitative testing in ‘real world’ use. Second, there is the extent of haemolysis in (a) hemizygote and homozygote patients and (b) heterozygotes with different G6PD deficiency variants. No G6PD deficient patient should receive tafenoquine with current quantitative testing. So ideally these dangerous events will not occur, but mistakes will happen. There are no available data on how frequently testing mistakes will occur. We also have no evidence to compare the subsequent haemolytic risks between the 5 mg/kg and 7.5 mg/kg doses.

Discussion

Sharma et al. state that ‘off-label use of a dose not robustly evaluated in clinical trials would pose a considerable risk to patient safety’. We have not recommended ‘off-label’ use of higher doses of tafenoquine. Our main recommendation was that clinical trials of higher doses should be conducted with the aim of providing optimal efficacy in patients at greatest risk of relapse.

Sharma et al. mention that ‘single doses of tafenoquine 300 mg and 600 mg had similar relapse-free efficacy at 6 months (89.2% and 91.9%, respectively)’ in the DETECTIVE Phase 2b study. As we noted above, this ignores variation in body weight and is based on a small sample size. Our pooled individual patient data meta-analysis suggests a substantial difference in efficacy between 5 and 10 mg/kg doses (Watson et al., 2022).

Conclusion

The individual patient data pharmacometric meta-analysis of the tafenoquine pre-registration studies provides an evidence-based characterisation of the dose-response relationship for radical curative efficacy in vivax malaria. The results demonstrate clearly that when using the current 5 mg/kg regimen a substantial proportion of adults will be under-dosed, and therefore that there would be a substantial benefit from increasing the dose to 7.5 mg/kg. There is no need to wait for ‘real-world evidence’ to confirm this finding. The primary concern is safety: what would happen if a G6PD deficient patient was given tafenoquine radical cure by mistake? In this scenario the relative haemolytic risks for the 5 mg/kg and 7.5 mg/kg are not known. The development and regulatory approval of tafenoquine has provided a critical alternative for vivax radical cure in endemic countries. Our analysis supports the need for further prospective clinical trials of higher tafenoquine doses to characterise their efficacy, safety and tolerability.

Data availability

The data used in this study can be accessed by submitting a research proposal via https://www.clinicalstudydatarequest.com/ using the following study codes: GSK-TAF112582; GSK-200951; GSK-TAF116564. Decisions to share data with independent researchers are made via an Independent Review Panel. All code used to process the data is available on GitHub (copy archived at Watson, 2023).

References

Decision letter

  1. Urszula Krzych
    Reviewing Editor; Walter Reed Army Institute of Research, United States
  2. Dominique Soldati-Favre
    Senior Editor; University of Geneva, Switzerland

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your work entitled "Response to the comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'" for further consideration by eLife. Your revised article has been evaluated by Dominique Soldati-Favre (as Senior Editor), Urszula Krzych (as Reviewing Editor), and a Reviewer (who has chosen to remain anonymous).

Please consider the comments and suggestions made by the Reviewer (please see below) and respond accordingly. We will also write to you separately about some editorial issues that need to be addressed.

Reviewer #1:

I have reviewed:

i) the comment from Sharma et al at GSK about the original eLife paper by Watson et al

ii) the response from Watson et al to the comment from Sharma et al.

I think both letters should be published substantially as they appear currently.

I do not agree with everything in Sharma et al regarding their defense of the original dosing regimen of 300mg Tafenoquine (plus chloroquine). In particular, Sharma et al shows an acute (hyper) sensitivity to safety issues which should be moot if the drug is truly given only to those who have been tested for G6PD deficiency. To base one's argument solely on those who are failing to meet this stated standard seems unusually strict especially when there are valid arguments for a higher dose for efficacy.

I also disagree with Watson's point "that tafenoquine is fundamentally a more dangerous drug". Yes, it is only given as a single dose which cannot be withdrawn, but tafenoquine's slow metabolism to the redox active form means that severe hemolytic events are very unlikely even if given inadvertently to G6PD deficient persons. There is a difference between grams of hemoglobin lost gradually over days and the more dangerous sudden hemolytic event which can cascade into a crisis. I would argue that primaquine is actually more likely to produce a dangerous event in those who hyper metabolize a single dose in a G6PD deficient person.

Arguments about efficacy are largely limited to SE Asia/Oceania and I find it strange that neither letter states that tropical Asian vivax will require more tafenoquine than other geographic areas since this is well known with its primaquine predecessor. Using the total drug data set which includes mostly Latin American studies to argue against increasing the drug regimen in SE Asia seems disingenuous. I really think the arguments should be focused on the rapidly and frequently relapsing malaria of SE Asia as that is the actual clinical problem. Sharma et al should not be diluting the issue with efficacy data mostly from Latin America as that is not where the problem is located.

Methaemoglobin (MetHb) may not be a validated endpoint but it is an important indicator of redox active metabolism. GSK's initial error with tafenoquine was to regard the drug as not metabolized on the basis of in vitro liver microsome studies. The INSPECTOR study [1] clearly indicates no efficacy against relapse when tafenoquine is combined not with chloroquine, but artemisinin. MetHb is the critical marker, likely of drug metabolism to a redox active intermediate. I think it is highly likely that INSPECTOR reflects lack of metabolism to the 5,6 orthoquinone and substantially reinforces Watson's argument that more studies are needed.

As such additional studies are evidently in process (a DSMB is being formed), it seems that both letters should reflect that more data is needed specifically focused on areas with frequently relapsing vivax malaria (SE Asia) in order to better define whether a higher dose regimen of tafenoquine is indicated or not.

[1] Sutanto I, et al. 2023 The Lancet Infectious Diseases. DOI: https://doi.org/10.1016/S1473-3099(23)00213-X

Editorial issues to be addressed:

Please find attached a revised version of the Scientific Correspondence article by Sharma et al. about your 2022 paper in eLife, along with a document containing a response from Sharma et al to a number of editorial queries from me.

Can you now please make the following revisions to your article.

# Please address the comments made by the reviewer.

# I asked Sharma et al to revise their article in response to the comments on lines 61-63, 86-89, 170-175, and 187-190 of your article. They have made some changes as a result of this request, so please revise your article accordingly.

# Sharma et al also made a number of comments on your article, I would be grateful if you could - as they request - revise lines 51-52 to avoid the term "more dangerous drug". You are free to revise your article in response to their other comments if you wish, but this is not essential.

# Please also make the following editorial changes

Abstract: Please reword as follows.

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, 5 mg/kg) is insufficient for cure in all adults, and that a 50% increase to 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 et al. defend the currently recommended adult dose of 5 mg/kg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2023). We contend that the relative haemolytic risks of the 5 mg/kg and 7.5 mg/kg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 5 mg/kg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.

https://doi.org/10.7554/eLife.91283.sa1

Author response

Reviewer comments:

We thank the reviewer for reading our reply in detail.

“I also disagree with Watson’s point “that tafenoquine is fundamentally a more dangerous drug”. Yes, it is only given as a single dose which cannot be withdrawn, but tafenoquine’s slow metabolism to the redox active form means that severe hemolytic events are very unlikely even if given inadvertently to G6PD deficient persons. There is a difference between grams of hemoglobin lost gradually over days and the more dangerous sudden hemolytic event which can cascade into a crisis. I would argue that primaquine is actually more likely to produce a dangerous event in those who hyper metabolize a single dose in a G6PD deficient person.”

We agree that this phrasing was too strong. Although 8-aminoquinoline induced haemolysis is inevitable in G6PD deficiency, the extent of haemolysis is highly variable. We do not know how a G6PD hemi or homozygote would response to a high tafenoquine dose. Although we agree the metabolism is slower, this remains an open question and as such tafenoquine should be considered highly dangerous in G6PD deficiency.

Editorial comments:

We have made all the requested changes, apart from two points:

• In the abstract we have kept “Sharma et al, representing the pharmaceutical company GSK”: it is important to point out that this criticism has a clear conflict of interest. This point is especially relevant now that the authors from MMV have removed their names from the letter.

• We have changed “tafenoquine is fundamentally a more dangerous drug” to “Compared with primaquine, the most widely used 8-aminoquinoline antimalarial, tafenoquine, if not used appropriately, may have a higher risk of causing severe haemolysis.”. See reply to reviewer above.

https://doi.org/10.7554/eLife.91283.sa2

Article and author information

Author details

  1. James A Watson

    1. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh, Viet Nam
    2. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    3. WorldWide Antimalarial Resistance Network, Oxford, United Kingdom
    Contribution
    Conceptualization, Writing – original draft, Writing – review and editing
    For correspondence
    james@tropmedres.ac
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  2. Robert J Commons

    1. WorldWide Antimalarial Resistance Network, Oxford, United Kingdom
    2. Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3359-5632
  3. Joel Tarning

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-4030
  4. Julie A Simpson

    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2660-2013
  5. Alejandro Llanos Cuentas

    Unit of Leishmaniasis and Malaria, Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia, San Martín de Porres, Peru
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7567-5534
  6. Marcus VG Lacerda

    Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3374-9985
  7. Justin A Green

    GSK, Brentford, United Kingdom
    Present address
    AstraZeneca, Cambridge, United Kingdom
    Contribution
    Writing – review and editing
    Competing interests
    Former employee of GSK; shareholder in GSK
  8. Gavin CKW Koh

    Department of Infectious Diseases, Northwick Park Hospital, Harrow, United Kingdom
    Contribution
    Writing – review and editing
    Competing interests
    Former employee of GSK; shareholder in GSK
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7336-1566
  9. Cindy S Chu

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. Shoklo Malaria Research Unit, Mae Sot, Thailand
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9465-8214
  10. François H Nosten

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. Shoklo Malaria Research Unit, Mae Sot, Thailand
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7951-0745
  11. Richard N Price

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. WorldWide Antimalarial Resistance Network, Oxford, United Kingdom
    3. Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2000-2874
  12. Nicholas PJ Day

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Contribution
    Writing – review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2309-1171
  13. Nicholas J White

    1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
    2. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Contribution
    Writing – original draft, Writing – review and editing
    For correspondence
    nickw@tropmedres.ac
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978

Funding

Wellcome Trust (093956/Z/10/C)

  • Nicholas J White

Wellcome Trust (223253/Z/21/Z)

  • James A Watson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

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).

Senior Editor

  1. Dominique Soldati-Favre, University of Geneva, Switzerland

Reviewing Editor

  1. Urszula Krzych, Walter Reed Army Institute of Research, United States

Version history

  1. Received: August 14, 2023
  2. Accepted: January 8, 2024
  3. Version of Record published: February 7, 2024 (version 1)

Copyright

© 2024, Watson et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. James A Watson
  2. Robert J Commons
  3. Joel Tarning
  4. Julie A Simpson
  5. Alejandro Llanos Cuentas
  6. Marcus VG Lacerda
  7. Justin A Green
  8. Gavin CKW Koh
  9. Cindy S Chu
  10. François H Nosten
  11. Richard N Price
  12. Nicholas PJ Day
  13. Nicholas J White
(2024)
Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'
eLife 13:e91283.
https://doi.org/10.7554/eLife.91283

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https://doi.org/10.7554/eLife.91283

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    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    James A Watson, Robert J Commons ... Nicholas J White
    Research Article Updated

    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 1102 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 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) 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.

    1. Epidemiology and Global Health
    David Robert Grimes
    Research Advance Updated

    In biomedical science, it is a reality that many published results do not withstand deeper investigation, and there is growing concern over a replicability crisis in science. Recently, Ellipse of Insignificance (EOI) analysis was introduced as a tool to allow researchers to gauge the robustness of reported results in dichotomous outcome design trials, giving precise deterministic values for the degree of miscoding between events and non-events tolerable simultaneously in both control and experimental arms (Grimes, 2022). While this is useful for situations where potential miscoding might transpire, it does not account for situations where apparently significant findings might result from accidental or deliberate data redaction in either the control or experimental arms of an experiment, or from missing data or systematic redaction. To address these scenarios, we introduce Region of Attainable Redaction (ROAR), a tool that extends EOI analysis to account for situations of potential data redaction. This produces a bounded cubic curve rather than an ellipse, and we outline how this can be used to identify potential redaction through an approach analogous to EOI. Applications are illustrated, and source code, including a web-based implementation that performs EOI and ROAR analysis in tandem for dichotomous outcome trials is provided.