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Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be...

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Autores principales: Mukaka, Mavuto, Onyamboko, Marie A., Olupot-Olupot, Peter, Peerawaranun, Pimnara, Suwannasin, Kanokon, Pagornrat, Watcharee, Kouhathong, Jindarat, Madmanee, Wanassanan, Were, Winifred, Namayanja, Cate, Onyas, Peter, Titin, Harriet, Baseke, Joy, Muhindo, Rita, Kayembe, Daddy K., Ndjowo, Pauline O., Basara, Benjamin B., Bongo, Georgette S., Okalebo, Charles B., Abongo, Grace, Uyoga, Sophie, Williams, Thomas N., Taya, Chiraporn, Dhorda, Mehul, Dondorp, Arjen M., Waithira, Naomi, Imwong, Mallika, Maitland, Kathryn, Fanello, Caterina, Day, Nicholas P.J., Tarning, Joel, White, Nicholas J., Taylor, Walter R.J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550634/
https://www.ncbi.nlm.nih.gov/pubmed/37757570
http://dx.doi.org/10.1016/j.ebiom.2023.104805
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author Mukaka, Mavuto
Onyamboko, Marie A.
Olupot-Olupot, Peter
Peerawaranun, Pimnara
Suwannasin, Kanokon
Pagornrat, Watcharee
Kouhathong, Jindarat
Madmanee, Wanassanan
Were, Winifred
Namayanja, Cate
Onyas, Peter
Titin, Harriet
Baseke, Joy
Muhindo, Rita
Kayembe, Daddy K.
Ndjowo, Pauline O.
Basara, Benjamin B.
Bongo, Georgette S.
Okalebo, Charles B.
Abongo, Grace
Uyoga, Sophie
Williams, Thomas N.
Taya, Chiraporn
Dhorda, Mehul
Dondorp, Arjen M.
Waithira, Naomi
Imwong, Mallika
Maitland, Kathryn
Fanello, Caterina
Day, Nicholas P.J.
Tarning, Joel
White, Nicholas J.
Taylor, Walter R.J.
author_facet Mukaka, Mavuto
Onyamboko, Marie A.
Olupot-Olupot, Peter
Peerawaranun, Pimnara
Suwannasin, Kanokon
Pagornrat, Watcharee
Kouhathong, Jindarat
Madmanee, Wanassanan
Were, Winifred
Namayanja, Cate
Onyas, Peter
Titin, Harriet
Baseke, Joy
Muhindo, Rita
Kayembe, Daddy K.
Ndjowo, Pauline O.
Basara, Benjamin B.
Bongo, Georgette S.
Okalebo, Charles B.
Abongo, Grace
Uyoga, Sophie
Williams, Thomas N.
Taya, Chiraporn
Dhorda, Mehul
Dondorp, Arjen M.
Waithira, Naomi
Imwong, Mallika
Maitland, Kathryn
Fanello, Caterina
Day, Nicholas P.J.
Tarning, Joel
White, Nicholas J.
Taylor, Walter R.J.
author_sort Mukaka, Mavuto
collection PubMed
description BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (T(max)) and median areas under the drug concentration curves (AUC(0-last)) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC(0-last),which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the 10.13039/501100000265UK Medical Research Council, 10.13039/100010269Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.
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spelling pubmed-105506342023-10-06 Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria Mukaka, Mavuto Onyamboko, Marie A. Olupot-Olupot, Peter Peerawaranun, Pimnara Suwannasin, Kanokon Pagornrat, Watcharee Kouhathong, Jindarat Madmanee, Wanassanan Were, Winifred Namayanja, Cate Onyas, Peter Titin, Harriet Baseke, Joy Muhindo, Rita Kayembe, Daddy K. Ndjowo, Pauline O. Basara, Benjamin B. Bongo, Georgette S. Okalebo, Charles B. Abongo, Grace Uyoga, Sophie Williams, Thomas N. Taya, Chiraporn Dhorda, Mehul Dondorp, Arjen M. Waithira, Naomi Imwong, Mallika Maitland, Kathryn Fanello, Caterina Day, Nicholas P.J. Tarning, Joel White, Nicholas J. Taylor, Walter R.J. eBioMedicine Articles BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m–<1 y: 1.25 mg, 1–5 y: 2.5 mg, 6–9 y: 5 mg, 10–11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3–7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10–0.40 (median 0.21, IQR 0.16–0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3–447 (median 103.0, IQR 72.1–140.0) ng/mL between 1.0 and 8.0 (median 2) hours (T(max)) and median areas under the drug concentration curves (AUC(0-last)) 730.2 (6 m–<1 y, n = 12), 582.8 (1–5 y, n = 126), 871.1 (6–9 y, n = 80), and 931.0 (10–11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8–5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC(0-last),which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the 10.13039/501100000265UK Medical Research Council, 10.13039/100010269Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication. Elsevier 2023-09-25 /pmc/articles/PMC10550634/ /pubmed/37757570 http://dx.doi.org/10.1016/j.ebiom.2023.104805 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Articles
Mukaka, Mavuto
Onyamboko, Marie A.
Olupot-Olupot, Peter
Peerawaranun, Pimnara
Suwannasin, Kanokon
Pagornrat, Watcharee
Kouhathong, Jindarat
Madmanee, Wanassanan
Were, Winifred
Namayanja, Cate
Onyas, Peter
Titin, Harriet
Baseke, Joy
Muhindo, Rita
Kayembe, Daddy K.
Ndjowo, Pauline O.
Basara, Benjamin B.
Bongo, Georgette S.
Okalebo, Charles B.
Abongo, Grace
Uyoga, Sophie
Williams, Thomas N.
Taya, Chiraporn
Dhorda, Mehul
Dondorp, Arjen M.
Waithira, Naomi
Imwong, Mallika
Maitland, Kathryn
Fanello, Caterina
Day, Nicholas P.J.
Tarning, Joel
White, Nicholas J.
Taylor, Walter R.J.
Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title_full Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title_fullStr Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title_full_unstemmed Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title_short Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
title_sort pharmacokinetics of single low dose primaquine in ugandan and congolese children with falciparum malaria
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550634/
https://www.ncbi.nlm.nih.gov/pubmed/37757570
http://dx.doi.org/10.1016/j.ebiom.2023.104805
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