Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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
_version_ 1784844634181074944
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
work_keys_str_mv AT watsonjamesa theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT commonsrobertj theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT tarningjoel theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT simpsonjuliea theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT llanoscuentasalejandro theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT lacerdamarcusvg theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT greenjustina theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT kohgavinckw theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT chucindys theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT nostenfrancoish theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT pricerichardn theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT daynicholaspj theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT whitenicholasj theclinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT watsonjamesa clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT commonsrobertj clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT tarningjoel clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT simpsonjuliea clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT llanoscuentasalejandro clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT lacerdamarcusvg clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT greenjustina clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT kohgavinckw clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT chucindys clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT nostenfrancoish clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT pricerichardn clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT daynicholaspj clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis
AT whitenicholasj clinicalpharmacologyoftafenoquineintheradicalcureofplasmodiumvivaxmalariaanindividualpatientdatametaanalysis