Abstract

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

Mukaka, M. Onyamboko, M. A. Olupot-Olupot, P. Peerawaranun, P. Suwannasin, K. Pagornrat, W. Kouhathong, J. Madmanee, W. Were, W. Namayanja, C. Onyas, P. Titin, H. Baseke, J. Muhindo, R. Kayembe, D. K. Ndjowo, P. O. Basara, B. B. Bongo, G. S. Okalebo, C. B. Abongo, G. Uyoga, S. Williams, T. N. Taya, C. Dhorda, M. Dondorp, A. M. Waithira, N. Imwong, M. Maitland, K. Fanello, C. Day, N. P. J. Tarning, J. White, N. J. Taylor, W. R. J.
EBioMedicine. 2023; 96104805

Permanent descriptor

https://doi.org/10.1016/j.ebiom.2023.104805

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 (T(1/2)) 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 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.