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The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis
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 i...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9725750/ https://www.ncbi.nlm.nih.gov/pubmed/36472067 http://dx.doi.org/10.7554/eLife.83433 |
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author | Watson, James A Commons, Robert J Tarning, Joel Simpson, Julie A Llanos Cuentas, Alejandro Lacerda, Marcus VG Green, Justin A Koh, Gavin CKW Chu, Cindy S Nosten, François H Price, Richard N Day, Nicholas PJ White, Nicholas J |
author_facet | Watson, James A Commons, Robert J Tarning, Joel Simpson, Julie A Llanos Cuentas, Alejandro Lacerda, Marcus VG Green, Justin A Koh, Gavin CKW Chu, Cindy S Nosten, François H Price, Richard N Day, Nicholas PJ White, Nicholas J |
author_sort | Watson, James A |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9725750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-97257502022-12-07 The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis Watson, James A Commons, Robert J Tarning, Joel Simpson, Julie A Llanos Cuentas, Alejandro Lacerda, Marcus VG Green, Justin A Koh, Gavin CKW Chu, Cindy S Nosten, François H Price, Richard N Day, Nicholas PJ White, Nicholas J eLife Epidemiology and Global Health 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. eLife Sciences Publications, Ltd 2022-12-06 /pmc/articles/PMC9725750/ /pubmed/36472067 http://dx.doi.org/10.7554/eLife.83433 Text en © 2022, Watson, Commons et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Epidemiology and Global Health Watson, James A Commons, Robert J Tarning, Joel Simpson, Julie A Llanos Cuentas, Alejandro Lacerda, Marcus VG Green, Justin A Koh, Gavin CKW Chu, Cindy S Nosten, François H Price, Richard N Day, Nicholas PJ White, Nicholas J The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title | The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title_full | The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title_fullStr | The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title_full_unstemmed | The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title_short | The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis |
title_sort | clinical pharmacology of tafenoquine in the radical cure of plasmodium vivax malaria: an individual patient data meta-analysis |
topic | Epidemiology and Global Health |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9725750/ https://www.ncbi.nlm.nih.gov/pubmed/36472067 http://dx.doi.org/10.7554/eLife.83433 |
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