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...
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| Format: | Article |
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eLife Sciences Publications Ltd
2022-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83433 |
| _version_ | 1811311513242173440 |
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| author | James A Watson Robert J Commons Joel Tarning Julie A Simpson Alejandro Llanos Cuentas Marcus VG Lacerda Justin A Green Gavin CKW Koh Cindy S Chu François H Nosten Richard N Price Nicholas PJ Day Nicholas J White |
| author_facet | James A Watson Robert J Commons Joel Tarning Julie A Simpson Alejandro Llanos Cuentas Marcus VG Lacerda Justin A Green Gavin CKW Koh Cindy S Chu François H Nosten Richard N Price Nicholas PJ Day Nicholas J White |
| author_sort | James A Watson |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T10:20:13Z |
| format | Article |
| id | doaj.art-f5567952f4604510b3632a25a317789f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T10:20:13Z |
| publishDate | 2022-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f5567952f4604510b3632a25a317789f2022-12-22T02:50:33ZengeLife Sciences Publications LtdeLife2050-084X2022-12-011110.7554/eLife.83433The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysisJames A Watson0https://orcid.org/0000-0001-5524-0325Robert J Commons1https://orcid.org/0000-0002-3359-5632Joel Tarning2https://orcid.org/0000-0003-4566-4030Julie A Simpson3https://orcid.org/0000-0002-2660-2013Alejandro Llanos Cuentas4Marcus VG Lacerda5Justin A Green6Gavin CKW Koh7Cindy S Chu8François H Nosten9https://orcid.org/0000-0002-7951-0745Richard N Price10https://orcid.org/0000-0003-2000-2874Nicholas PJ Day11https://orcid.org/0000-0003-2309-1171Nicholas J White12https://orcid.org/0000-0002-1897-1978Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; WorldWide Antimalarial Resistance Network, Oxford, United KingdomWorldWide Antimalarial Resistance Network, Oxford, United Kingdom; Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, AustraliaCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, AustraliaUnit of Leishmaniasis and Malaria, Instituto de Medicina Tropical “Alexander von Humboldt”, Universidad Peruana Cayetano Heredia, Lima, PeruFundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, BrazilFormerly Senior Director, Global Health, GlaxoSmithKline, Brentford, United KingdomDepartment of Infectious Diseases, Northwick Park Hospital, Harrow, United KingdomCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Shoklo Malaria Research Unit, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, ThailandCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Shoklo Malaria Research Unit, Mahidol–Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, ThailandCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; WorldWide Antimalarial Resistance Network, Oxford, United Kingdom; Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, AustraliaCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandTafenoquine 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.https://elifesciences.org/articles/83433tafenoquineradical curePlasmodium vivaxhaemolysis |
| spellingShingle | James A Watson Robert J Commons Joel Tarning Julie A Simpson Alejandro Llanos Cuentas Marcus VG Lacerda Justin A Green Gavin CKW Koh Cindy S Chu François H Nosten Richard N Price Nicholas PJ Day Nicholas J White The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis eLife tafenoquine radical cure Plasmodium vivax haemolysis |
| 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 | tafenoquine radical cure Plasmodium vivax haemolysis |
| url | https://elifesciences.org/articles/83433 |
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