TY - JOUR
T1 - Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
AU - Mukaka, Mavuto
AU - Onyamboko, Marie A.
AU - Olupot-Olupot, Peter
AU - Peerawaranun, Pimnara
AU - Suwannasin, Kanokon
AU - Pagornrat, Watcharee
AU - Kouhathong, Jindarat
AU - Madmanee, Wanassanan
AU - Were, Winifred
AU - Namayanja, Cate
AU - Onyas, Peter
AU - Titin, Harriet
AU - Baseke, Joy
AU - Muhindo, Rita
AU - Kayembe, Daddy K.
AU - Ndjowo, Pauline O.
AU - Basara, Benjamin B.
AU - Bongo, Georgette S.
AU - Okalebo, Charles B.
AU - Abongo, Grace
AU - Uyoga, Sophie
AU - Williams, Thomas N.
AU - Taya, Chiraporn
AU - Dhorda, Mehul
AU - Dondorp, Arjen M.
AU - Waithira, Naomi
AU - Imwong, Mallika
AU - Maitland, Kathryn
AU - Fanello, Caterina
AU - Day, Nicholas P. J.
AU - Tarning, Joel
AU - White, Nicholas J.
AU - Taylor, Walter R. J.
N1 - Funding Information: WRT, MM and JT are supported by the Wellcome Trust of Great Britain through its core grant (220211) to the Mahidol-Oxford Tropical Medicine Research Unit research programme . TNW is funded through a Senior Research Fellowship from Wellcome (202800/Z/16/Z) and NJW is a Wellcome Trust Principal Fellow. KM and Peter OO received funding from Wellcome East African Overseas Programme Award from the Wellcome Trust 203077/Z/16/Z. Funding Information: This work was cofunded by the UK Medical Research Council, Wellcome, 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. Publisher Copyright: © 2023 The Author(s)
PY - 2023/10/1
Y1 - 2023/10/1
N2 - 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 (Tmax) and median areas under the drug concentration curves (AUC0-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 AUC0-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 UK Medical Research Council, Wellcome 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.
AB - 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 (Tmax) and median areas under the drug concentration curves (AUC0-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 AUC0-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 UK Medical Research Council, Wellcome 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.
KW - Age-based dosing
KW - Plasmodium falciparum
KW - Primaquine
KW - Transmission blocking
UR - http://www.scopus.com/inward/record.url?scp=85172014951&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ebiom.2023.104805
DO - https://doi.org/10.1016/j.ebiom.2023.104805
M3 - Article
C2 - 37757570
SN - 2352-3964
VL - 96
JO - eBioMedicine
JF - eBioMedicine
M1 - 104805
ER -