The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis
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This competently performed retrospective analysis presents important findings concerning the clinical use of tafenoquine, a drug against Plasmodium vivax malaria. The assembly of the majority of global tafenoquine pharmacology data from clinical treatment studies provides compelling evidence in support of the drug's regimen that includes an increase in dosing, which would lead to a significant enhancement of the drug efficacy, hence a decrease in recurrent parasitemia. The manuscript could benefit from a more detailed analysis and discussion concerning the side effects of the drug affecting more susceptible populations.
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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 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.
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Author Response
Reviewer #1 (Public Review):
Tafenoquine is an important 8-aminoquinoline antimalarial, mostly aimed at the management of Plasmodium vivax malaria. Through the retrospective analysis of several previously performed efficacy trials, the authors aimed to better understand the drugs mechanism of action, while exploring the possibility of improved efficacy through dose increment.
Strengths: robust analysis approaches unlocked three main messages with the potential of improving the clinical practice:
i. P. vivax recurrency is positively associated with tafenoquine terminal half-life and D7 methemoglobin levels.
ii. The methemoglobin levels support the current view that tafenoquine, acts through its metabolites, similar to what is believed for primaquine.
ii. Most importantly, the therapeutic window of tafenoquine …
Author Response
Reviewer #1 (Public Review):
Tafenoquine is an important 8-aminoquinoline antimalarial, mostly aimed at the management of Plasmodium vivax malaria. Through the retrospective analysis of several previously performed efficacy trials, the authors aimed to better understand the drugs mechanism of action, while exploring the possibility of improved efficacy through dose increment.
Strengths: robust analysis approaches unlocked three main messages with the potential of improving the clinical practice:
i. P. vivax recurrency is positively associated with tafenoquine terminal half-life and D7 methemoglobin levels.
ii. The methemoglobin levels support the current view that tafenoquine, acts through its metabolites, similar to what is believed for primaquine.
ii. Most importantly, the therapeutic window of tafenoquine is wider than previously considered, allowing the suggestion of a significant increase in dosing, from 300 mg to 450 mg, leading to significantly increased efficacy.
Weaknesses: being a retrospective analysis, the work is limited to the available data. In particular, and as referred by the authors, no drug levels are reported. Additionally, there are some aspects that in my view need more detailed analysis and discussion, in particular, what seems to be a lack of exploration as to the importance (or lack of it) of the patient CYP2D6 status in Tafenoquine T1/2, methemoglobin levels, and overall efficacy. These mild weaknesses do not change the overall conclusions of the study.
We thank the reviewer for their positive comments.
The analysis estimates the parameters of the PK model from 4499 measured drug concentrations measured for 718 individuals between days 0 and 180. The active metabolites of tafenoquine are unknown and thus could not be quantified.
Whilst the study is retrospective it includes 77% (651/847) of all patients enrolled in published P. vivax treatment trials of tafenoquine.
We respond to the relationship between CYP2D6 polymorphisms and the other outcomes in our response to Reviewer #1, Comment 2.
Reviewer #3 (Public Review):
By assembling the vast majority of global tafenoquine pharmacology data from clinical treatment studies that led to the 8-aminoquinoline's registration in 2018, the authors of this manuscript have convincingly made their argument that the currently recommended treatment dosage of 300mg (in combination with chloroquine) is too low and needs to be increased by at least 50%. Access to the multiple data sets is thorough, the modelling reasonable and the conclusion reached is sound.
How did we get here (again) under-dosing malaria patients with a class of drugs we have been working on for a century? Speaking as someone who was associated with tafenoquine development over two decades, it seems that worry about adverse events, specifically hemolysis in G6PD deficient persons, overcame the operational requirement to give enough drugs in a single dose regimen. However, tafenoquine is very safe in G6PD normal persons who by definition were the ones entered into the clinical treatment trials. Risk-benefit judgments cannot always be weighted towards "safety" especially when the real concern was that a single severe adverse event would derail the entire development program. Real-world effectiveness matters and should now result in the studies the authors state are needed to certify the higher dose regimen.
- The schizophrenic nature of tafenoquine development needs to be mentioned. This manuscript discusses malaria treatment and includes nearly all the relevant data, but extensive work was also done to support the chemoprophylaxis indication largely sponsored by the US Army. These prophylaxis efforts were often separate from the parallel efforts on treatment indication to the loss of both groups who were ostensibly working on the same drug. 450mg tafenoquine is not a large dose; 600mg (over 3 days) is routinely given at the beginning of malaria chemoprophylaxis. Up to twice that amount was given in phase 2 studies done in Kenya in 1998 which resulted in the only described severe hemolytic reaction when one G6PD deficient heterozygote woman was given 1200mg over 3 days due to incorrect recording of her G6PD status. It is not easy to hemolyze even G6PD-deficient erythrocytes due to the slow metabolism of tafenoquine. Nearly all clinical trials of both primaquine and tafenoquine have experienced similar hemolytic events when there were errors in the determination of G6PD status. This does not mean that all 8-aminoquinolines are dangerous drugs, only that a known genetic polymorphism needs to be accounted for when treating vivax malaria.
It is notable that much larger doses of tafenoquine have been evaluated previously and these have been well tolerated in individuals with G6PD activity >30% (previous studies used semi-quantitative tests). We have added a review of all patients with P. vivax malaria who have been studied in treatment trials. A total of 847 were enrolled in all studies and our series contains individual patient data on 651 (77%) of these patients.
We have added the following to the Discussion on lines 277-283:
“Much larger doses have been studied in treatment and prophylaxis trials (up to 2100mg given over one week, Walsh et al., 1999, see Supplementary Appendix). The only report of a severe haemolytic reaction occurred in a female patient heterozygous for G6PD deficiency (A- variant) and received a total dose of 1200mg tafenoquine over 3 days (Shanks et al., 2001). In the same study, a homozygous female (A- variant) who was also given 1200mg tafenoquine over 3 days had an estimated 3g/dL drop in haemoglobin, but remained asymptomatic.”
- The authors point out the utility of 7-day methemoglobin concentrations in predicted drug success/failure in the prevention of subsequent relapses. This is important and stresses the requirement of drug metabolism to a redox-active intermediate as being a common property of all 8-aminoquinolines. Tafenoquine and primaquine are similar but not identical and the slow metabolism of tafenoquine to its redox-active intermediates explains its main advantage of being capable of supporting a single-dose cure. The main reason this was not appreciated much earlier is we were looking in the wrong place. Metabolic end-products (5,6 orthoquinones) are in very low concentrations after single-dose tafenoquine in the blood, but being water-soluble they are easily located in the urine. Such urine metabolites indicative of redox action are very likely to be complementary to methemoglobin measurements which mark the redox effect on the erythrocyte. Despite earlier simplifying assumptions made during tafenoquine development (no significant metabolites exist), metabolism to redox-active intermediates must be embraced as the explanation of drug efficacy and not a cause of undesirable adverse events.
Another dark cloud over tafenoquine mentioned by the authors was the very disappointing results of the INSPECTOR trial in Indonesia whose full results are yet to be published. The failure of P vivax relapse prevention using 300mg tafenoquine with dihydroartemisinin-piperaquine in Indonesian soldiers was largely ascribed to under-dosing. Although this may have been partially true, another aspect indicated in figure 15 of the appendix is the nature of the partner drug. Artemisinin combinations with tafenoquine do not produce the same amount of methaemoglobin (indicative of redox metabolism) as when combined with the registered partner drug chloroquine. We do not understand tafenoquine metabolism, but it is increasingly clear that what drug is combined with tafenoquine makes a very substantial difference. Despite the great operational desire to use artemisinin combination therapy for all malaria treatment regimens, this may not be possible with tafenoquine. Chloroquine likely is driving tafenoquine metabolism as it has no real effect on latent hypnozoites in the liver by itself. Increased dose studies with tafenoquine need to be done with chloroquine, not artemisinin.
We are aware that this is an area of intense interest and that ex vivo data were presented at the recent ASTMH conference in Seattle suggestive of a drug-drug interaction between artemisinisin and tafenoquine. However, there are as yet insufficient in-vivo data to conclude with tafenoquine reducing the methaemoglobin concentration indicative of reducing redox metabolism compared to chloroquine and tafenoquine. In addition these data as yet unpublished.
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eLife assessment
This competently performed retrospective analysis presents important findings concerning the clinical use of tafenoquine, a drug against Plasmodium vivax malaria. The assembly of the majority of global tafenoquine pharmacology data from clinical treatment studies provides compelling evidence in support of the drug's regimen that includes an increase in dosing, which would lead to a significant enhancement of the drug efficacy, hence a decrease in recurrent parasitemia. The manuscript could benefit from a more detailed analysis and discussion concerning the side effects of the drug affecting more susceptible populations.
-
Reviewer #1 (Public Review):
Tafenoquine is an important 8-aminoquinoline antimalarial, mostly aimed at the management of Plasmodium vivax malaria. Through the retrospective analysis of several previously performed efficacy trials, the authors aimed to better understand the drugs mechanism of action, while exploring the possibility of improved efficacy through dose increment.
Strengths: robust analysis approaches unlocked three main messages with the potential of improving the clinical practice:
i. P. vivax recurrency is positively associated with tafenoquine terminal half-life and D7 methemoglobin levels.
ii. The methemoglobin levels support the current view that tafenoquine, acts through its metabolites, similar to what is believed for primaquine.
ii. Most importantly, the therapeutic window of tafenoquine is wider than previously …Reviewer #1 (Public Review):
Tafenoquine is an important 8-aminoquinoline antimalarial, mostly aimed at the management of Plasmodium vivax malaria. Through the retrospective analysis of several previously performed efficacy trials, the authors aimed to better understand the drugs mechanism of action, while exploring the possibility of improved efficacy through dose increment.
Strengths: robust analysis approaches unlocked three main messages with the potential of improving the clinical practice:
i. P. vivax recurrency is positively associated with tafenoquine terminal half-life and D7 methemoglobin levels.
ii. The methemoglobin levels support the current view that tafenoquine, acts through its metabolites, similar to what is believed for primaquine.
ii. Most importantly, the therapeutic window of tafenoquine is wider than previously considered, allowing the suggestion of a significant increase in dosing, from 300 mg to 450 mg, leading to significantly increased efficacy.Weaknesses: being a retrospective analysis, the work is limited to the available data. In particular, and as referred by the authors, no drug levels are reported. Additionally, there are some aspects that in my view need more detailed analysis and discussion, in particular, what seems to be a lack of exploration as to the importance (or lack of it) of the patient CYP2D6 status in Tafenoquine T1/2, methemoglobin levels, and overall efficacy. These mild weaknesses do not change the overall conclusions of the study.
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Reviewer #2 (Public Review):
The current treatment for the radical cure of Plasmodium vivax malaria is primaquine, it was first made available in the 1950s and there is a need for better treatments. Recently a new drug was licensed, tafenoquine. Tafenoquine is a single-dose treatment due to the drug's long half-life. The expected increase in treatment adherence is an important advantage, however, the drug's slow elimination has also a drawback. Patients must be tested for a ubiquitous enzyme (glucose-6-phosphate dehydrogenase) deficiency prior to treatment, as the use of this drug in the G6DP deficient population could lead to life-threatening haemolysis. Implementing accurate quantitative testing in remote malaria-endemic areas is challenging. Providing point-of-care test equipment, supplies and training may not be cost-effective as …
Reviewer #2 (Public Review):
The current treatment for the radical cure of Plasmodium vivax malaria is primaquine, it was first made available in the 1950s and there is a need for better treatments. Recently a new drug was licensed, tafenoquine. Tafenoquine is a single-dose treatment due to the drug's long half-life. The expected increase in treatment adherence is an important advantage, however, the drug's slow elimination has also a drawback. Patients must be tested for a ubiquitous enzyme (glucose-6-phosphate dehydrogenase) deficiency prior to treatment, as the use of this drug in the G6DP deficient population could lead to life-threatening haemolysis. Implementing accurate quantitative testing in remote malaria-endemic areas is challenging. Providing point-of-care test equipment, supplies and training may not be cost-effective as the efficacy of tafenoquine has not been proven non-inferior to primaquine.
Thus strategies to increase tafenoquine efficacy are of paramount importance to raise the public health relevance of the first new drug developed for the radical cure of vivax malaria in the last 70 years. This paper polled together and analysed the clinical information of participants of the tafenoquine clinical trials, and using models they evaluated the influence of dose per weight on the recurrence rate of the disease. They predict that the tafenoquine efficacy would surpass the primaquine one if the tafenoquine dose was increased. They also correlated the levels of methaemoglobin production and the reduction of relapses, implying that methaemoglobin can be a surrogate marker of efficacy.
As with any model prediction, these results should be confirmed in clinical trials, especially the safety profile of the suggested regimen. The surrogate marker of oxidative drug activity is a very interesting indirect efficacy measurement, although it is limited to any indirect outcome. Even the vivax recurrence rate itself has limitations as vivax relapse and reinfection cannot be differentiated. Still, these results provide a solid support for future clinical trials that might reinforce the public health relevance of tafenoquine.
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Reviewer #3 (Public Review):
By assembling the vast majority of global tafenoquine pharmacology data from clinical treatment studies that led to the 8-aminoquinoline's registration in 2018, the authors of this manuscript have convincingly made their argument that the currently recommended treatment dosage of 300mg (in combination with chloroquine) is too low and needs to be increased by at least 50%. Access to the multiple data sets is thorough, the modelling reasonable and the conclusion reached is sound.
How did we get here (again) under-dosing malaria patients with a class of drugs we have been working on for a century? Speaking as someone who was associated with tafenoquine development over two decades, it seems that worry about adverse events, specifically hemolysis in G6PD deficient persons, overcame the operational requirement to …
Reviewer #3 (Public Review):
By assembling the vast majority of global tafenoquine pharmacology data from clinical treatment studies that led to the 8-aminoquinoline's registration in 2018, the authors of this manuscript have convincingly made their argument that the currently recommended treatment dosage of 300mg (in combination with chloroquine) is too low and needs to be increased by at least 50%. Access to the multiple data sets is thorough, the modelling reasonable and the conclusion reached is sound.
How did we get here (again) under-dosing malaria patients with a class of drugs we have been working on for a century? Speaking as someone who was associated with tafenoquine development over two decades, it seems that worry about adverse events, specifically hemolysis in G6PD deficient persons, overcame the operational requirement to give enough drugs in a single dose regimen. However, tafenoquine is very safe in G6PD normal persons who by definition were the ones entered into the clinical treatment trials. Risk-benefit judgments cannot always be weighted towards "safety" especially when the real concern was that a single severe adverse event would derail the entire development program. Real-world effectiveness matters and should now result in the studies the authors state are needed to certify the higher dose regimen.
The schizophrenic nature of tafenoquine development needs to be mentioned. This manuscript discusses malaria treatment and includes nearly all the relevant data, but extensive work was also done to support the chemoprophylaxis indication largely sponsored by the US Army. These prophylaxis efforts were often separate from the parallel efforts on treatment indication to the loss of both groups who were ostensibly working on the same drug. 450mg tafenoquine is not a large dose; 600mg (over 3 days) is routinely given at the beginning of malaria chemoprophylaxis. Up to twice that amount was given in phase 2 studies done in Kenya in 1998 which resulted in the only described severe hemolytic reaction when one G6PD deficient heterozygote woman was given 1200mg over 3 days due to incorrect recording of her G6PD status. It is not easy to hemolyze even G6PD-deficient erythrocytes due to the slow metabolism of tafenoquine. Nearly all clinical trials of both primaquine and tafenoquine have experienced similar hemolytic events when there were errors in the determination of G6PD status. This does not mean that all 8-aminoquinolines are dangerous drugs, only that a known genetic polymorphism needs to be accounted for when treating vivax malaria.
The authors point out the utility of 7-day methemoglobin concentrations in predicted drug success/failure in the prevention of subsequent relapses. This is important and stresses the requirement of drug metabolism to a redox-active intermediate as being a common property of all 8-aminoquinolines. Tafenoquine and primaquine are similar but not identical and the slow metabolism of tafenoquine to its redox-active intermediates explains its main advantage of being capable of supporting a single-dose cure. The main reason this was not appreciated much earlier is we were looking in the wrong place. Metabolic end-products (5,6 orthoquinones) are in very low concentrations after single-dose tafenoquine in the blood, but being water-soluble they are easily located in the urine. Such urine metabolites indicative of redox action are very likely to be complementary to methemoglobin measurements which mark the redox effect on the erythrocyte. Despite earlier simplifying assumptions made during tafenoquine development (no significant metabolites exist), metabolism to redox-active intermediates must be embraced as the explanation of drug efficacy and not a cause of undesirable adverse events.
Another dark cloud over tafenoquine mentioned by the authors was the very disappointing results of the INSPECTOR trial in Indonesia whose full results are yet to be published. The failure of P vivax relapse prevention using 300mg tafenoquine with dihydroartemisinin-piperaquine in Indonesian soldiers was largely ascribed to under-dosing. Although this may have been partially true, another aspect indicated in figure 15 of the appendix is the nature of the partner drug. Artemisinin combinations with tafenoquine do not produce the same amount of methemoglobin (indicative of redox metabolism) as when combined with the registered partner drug chloroquine. We do not understand tafenoquine metabolism, but it is increasingly clear that what drug is combined with tafenoquine makes a very substantial difference. Despite the great operational desire to use artemisinin combination therapy for all malaria treatment regimens, this may not be possible with tafenoquine. Chloroquine likely is driving tafenoquine metabolism as it has no real effect on latent hypnozoites in the liver by itself. Increased dose studies with tafenoquine need to be done with chloroquine, not artemisinin.
Treatment of P vivax malaria to prevent relapse by tafenoquine is the first but not the only indication of this long-acting 8-aminoquinoline. Besides chemoprophylaxis, tafenoquine has also been recently shown in controlled human challenges and field studies in Africa to block transmission at very low dosage regimens. If we are to realize tafenoquine's potential to block transmission in a population to eliminate malaria, we first have to get the treatment regimen and its combination partner right. This paper is another good step along the road to really understanding how to use this new antimalarial drug.
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