Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial

doi:10.1016/S2352-4642(21)00328-X

The Lancet Child & Adolescent Health

Volume 6, Issue 2, February 2022, Pages 86-95

https://doi.org/10.1016/S2352-4642(21)00328-X Get rights and content

Summary

Background

Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax.

Methods

This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2–15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration–time curve extrapolated to infinity (AUC_[0–∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496.

Findings

Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC_(0–∞) was 73·8 (90% prediction interval [PI] 46·9–117·0) μg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4–139·0) μg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9–174·0) μg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6–151·0) μg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6–98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study.

Interpretation

For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting.

Funding

GlaxoSmithKline and Medicines for Malaria Venture.

Translations

For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Introduction

More than 4 billion people are at risk of Plasmodium vivax malaria across Asia, Central and South America, Oceania, and the horn of Africa.¹ Children bear the greatest disease burden, particularly in high transmission areas.²

The lifecycle of P vivax is complex, including an acute blood-stage infection associated with symptomatic malaria and a dormant hypnozoite liver stage. Antimalarial drugs used to treat acute malaria are ineffective against hypnozoites, which persist in the host undetected.³ Periodic hypnozoite reactivation causes repeated clinical malaria episodes weeks or months after the initial infectious inoculation.³ These relapses contribute to transmission and impede malaria control and elimination efforts.¹ Repeated relapses in children can cause anaemia,⁴ increasing susceptibility to other illnesses, and delaying physical and cognitive development.⁵

Research in context

Evidence before this study

We searched ClinicalTrials.gov for trials listed from the inception of the database to April 4, 2021, using the search terms “tafenoquine” AND “children”, with no language restrictions. Four registered studies were identified, none of which investigated tafenoquine for Plasmodium vivax relapse prevention in patients younger than 16 years with uncomplicated malaria. We also searched PubMed using the search terms “tafenoquine” AND “clinical trial” from inception of the database to April 4, 2021. We identified 35 studies, none of which included patients or healthy volunteers younger than 16 years. Three randomised clinical trials of single-dose tafenoquine 300 mg with chloroquine for P vivax malaria relapse prevention in adults were found. However, there are no planned studies or published references that evaluate a tafenoquine paediatric dosing regimen for the prevention of P vivax malaria relapse. A published population pharmacokinetic model developed using the efficacious drug exposure from adults administered the 300 mg tafenoquine approved dose was used to predict the initial dosing regimens in children evaluated in this study.

Added value of this study

This is the first study to assess tafenoquine pharmacokinetics, recurrence-free efficacy, and safety, including the use of a new paediatric dispersible formulation, for radical cure of P vivax malaria in children.

Implications of all the available evidence

Tafenoquine, including the dispersible formulation, had exposures and efficacy in children with P vivax malaria consistent with observations in adolescents and adults. The safety profile was as expected based on data from adults with P vivax malaria, with the exception of post-dose vomiting, which was successfully mitigated. Single-dose antirelapse therapy with tafenoquine can promote dosing accuracy and improve adherence to P vivax malaria radical cure in children.

Radical cure of P vivax infection requires a schizonticide to resolve the acute blood-stage infection plus an 8-aminoquinoline (primaquine or tafenoquine) to target liver hypnozoites. Treatment options are chloroquine or artemisinin-based combination therapy plus primaquine or chloroquine plus tafenoquine. Because 8-aminoquinolines induce haemolysis in individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient, G6PD testing is necessary to exclude those at risk.⁶

Primaquine is the only relapse prevention therapy recommended for use in children (6 months to 15 years old).⁷ However, without a paediatric formulation, tablets must be cut or crushed, with the consequent risk of under or over dosing. The recommended primaquine treatment regimen is 14 days,⁷ with poor adherence compromising effectiveness.⁸ Furthermore, primaquine efficacy is impaired in patients with diminished cytochrome P450 2D6 activity.⁹

Tafenoquine is approved for P vivax malaria relapse prevention in patients aged 16 years old or older who have a G6PD activity more than 70% of the local population median.¹⁰ In randomised clinical trials, 3-day chloroquine plus single-dose tafenoquine (300 mg) prevented P vivax malaria relapse over 6 months by 70% relative to chloroquine alone,¹¹ and had a similar efficacy and safety profile to 3-day chloroquine plus 14-day (15 mg per day) primaquine.11, 12 Unlike primaquine, there is no clear evidence that tafenoquine efficacy is affected by cytochrome P450 2D6 phenotype.11, 12, 13, 14 We aimed to develop a paediatric single-dose P vivax malaria relapse prevention therapy and assess its safety and efficacy in children with P vivax malaria.

Section snippets

Study design and patients

This trial was an open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial done at three community health centres in Vietnam (Bac Ai Medical Centre, Bac Ai District, Ninh Thuan Province; Phuoc Long Medical Centre, Binh Phuoc Province; Khanh Vinh Medical Centre, Khanh Vinh District, Khanh Hoa Province), and one in Monteria, Colombia. Eligible patients were between 2 years and 15 years old, weighed 5 kg or more, had microscopically confirmed uncomplicated P

Results

Between Feb 6, 2017, and Feb 17, 2020, 60 patients with P vivax malaria aged 2–12 years, weighing 12·0–62·3 kg were enrolled and completed the study (figure 1; table 1; appendix 3 p 6).²¹ Baseline symptoms were consistent with malaria: with 43 (72%) of 60 patients had mild to moderate anaemia (table 1).²¹ Of note, 23 (38%) patients had vomiting and 16 (26%) had nausea at enrolment (appendix 3 p 6). 58 (97%) patients were successfully dosed with tafenoquine at doses of 4·8–12·5 mg/kg (appendix 3

Discussion

We assessed the use of single-dose tafenoquine, including a dispersible tablet formulation, for P vivax relapse prevention in children. A paediatric population pharmacokinetic model was developed to predict appropriate tafenoquine doses for children aged 6 months to 15 years who weighed 5 kg or more. Tafenoquine 4-month recurrence-free efficacy and the safety profile in children aged 2–15 years were consistent with previous reports, except for post-dose vomiting.11, 12, 22

Consistent with the

Data sharing

Anonymised individual participant data and study documents can be requested for future research online.

Declaration of interests

IDV and TTH report funding from GlaxoSmithKline and Medicines for Malaria Venture for the TEACH clinical trial. AM, HS, VMR, JJB, TBE, KR, MT, KM, SWJ, NG and LKT are employees of GlaxoSmithKline and hold shares in the company. JAG is a former employee of GlaxoSmithKline and holds shares in the company. SD is an employee of Medicines for Malaria Venture. All other authors declare no competing interests.

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Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the phase 2b DETECTIVE trial

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Cited by (12)

Tafenoquine co-administered with dihydroartemisinin–piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study
2023, The Lancet Infectious Diseases
Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin–piperaquine for the radical cure of P vivax malaria.
In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin–piperaquine alone, dihydroartemisinin–piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin–piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin–piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed.
Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4–22) in patients treated with dihydroartemisinin–piperaquine alone versus 21% (11–34) in patients treated with tafenoquine plus dihydroartemisinin–piperaquine (hazard ratio 0·44; 95% CI [0·29–0·69]) and 52% (37–65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin–piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin–piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin–piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively.
Although tafenoquine plus dihydroartemisinin–piperaquine was statistically superior to dihydroartemisinin–piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria.
ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK.
For the Indonesian translation of the abstract see Supplementary Materials section.
Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial
2022, The Lancet Microbe
Citation Excerpt :
A study in Gabon with various tafenoquine doses for prophylaxis in semi-immune children and young adults between 12 and 20 years of age reported similar adverse events between treatment groups and compared with the placebo group but an average reduction in haemoglobin concentrations compared with baseline of 0·4 mg/dL with the highest tafenoquine dose of 200 mg.32 Another phase 2 study assessed the safety and efficacy of chloroquine plus single weight-dependent doses of tafenoquine (100 mg, 150 mg, 200 mg, or 300 mg) in children aged between 2 and 15 years with P vivax malaria and G6PD enzyme activity of at least 70% in Columbia and Vietnam.33 The most common adverse events attributed to drug treatment were vomiting and asymptomatic methaemoglobin increases.
Tafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin–piperaquine for reducing gametocyte density and transmission to mosquitoes.
In this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12–50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin–piperaquine, or dihydroartemisinin–piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin–piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin–piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2020; the trial is registered with ClinicalTrials.gov, NCT04609098.
From Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64–35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15–100; p=0·0005 for difference from baseline) following dihydroartemisinin–piperaquine only, 100% (98·36–100; p=0·0005) following dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg, 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin–piperaquine n=2; dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups.
Tafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin–piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials.
Bill & Melinda Gates Foundation.
For the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.
Tafenoquine for children: a step towards implementation
2022, The Lancet Child and Adolescent Health
Comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'
2024, eLife
Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'
2024, eLife
Insights into the antimicrobial effects of tafenoquine against Enterococcus and its biofilms
2024, Journal of Applied Microbiology

View all citing articles on Scopus

^*: Authors contributed equally

^†: Authors contributed equally

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ArticlesTafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial

Summary

Background

Methods

Findings

Interpretation

Funding

Translations

Introduction

Section snippets

Study design and patients

Results

Discussion

Data sharing

Declaration of interests

Trends Parasitol

Lancet

Lancet

Global epidemiology of Plasmodium vivax

Am J Trop Med Hyg

Killing the hypnozoite—drug discovery approaches to prevent relapse in Plasmodium vivax

Pathog Glob Health

The anaemia of Plasmodium vivax malaria

Malar J

Malaria impact on cognitive function of children in a peri-urban community in the Brazilian Amazon

Malar J

Testing for G6PD deficiency for safe use of primaquine in radical cure of P vivax and P ovale

Guidelines for the treatment of malaria

Primaquine for preventing relapse in people with Plasmodium vivax malaria treated with chloroquine

Cochrane Database Syst Rev

Association of impaired cytochrome P450 2D6 activity genotype and phenotype with therapeutic efficacy of primaquine treatment for latent Plasmodium vivax malaria

JAMA Netw Open

KRINTAFEL (tafenoquine) tablets, for oral use; prescribing information

Single-dose tafenoquine to prevent relapse of Plasmodium vivax malaria

N Engl J Med

Tafenoquine versus primaquine to prevent relapse of Plasmodium vivax malaria

N Engl J Med

Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the phase 2b DETECTIVE trial

Malar J

Articles
Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial