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. 2023 Oct:96:104805.
doi: 10.1016/j.ebiom.2023.104805. Epub 2023 Sep 25.

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

Mavuto Mukaka  1 , Marie A Onyamboko  2 , Peter Olupot-Olupot  3 , Pimnara Peerawaranun  4 , Kanokon Suwannasin  4 , Watcharee Pagornrat  4 , Jindarat Kouhathong  4 , Wanassanan Madmanee  4 , Winifred Were  5 , Cate Namayanja  5 , Peter Onyas  5 , Harriet Titin  5 , Joy Baseke  5 , Rita Muhindo  5 , Daddy K Kayembe  2 , Pauline O Ndjowo  2 , Benjamin B Basara  2 , Georgette S Bongo  2 , Charles B Okalebo  5 , Grace Abongo  5 , Sophie Uyoga  6 , Thomas N Williams  7 , Chiraporn Taya  4 , Mehul Dhorda  1 , Arjen M Dondorp  1 , Naomi Waithira  1 , Mallika Imwong  8 , Kathryn Maitland  7 , Caterina Fanello  1 , Nicholas P J Day  1 , Joel Tarning  1 , Nicholas J White  1 , Walter R J Taylor  9
Affiliations

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

Mavuto Mukaka et al. EBioMedicine. 2023 Oct.

Abstract

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.

Keywords: Age-based dosing; Plasmodium falciparum; Primaquine; Transmission blocking.

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Conflict of interest statement

Declaration of interests All authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Disposition of primaquine and of carboxyprimaquine. a. Disposition of primaquine for all patients (n = 250). b. Disposition of carboxyprimaquine (n = 248).
Fig. 2
Fig. 2
Maximum primaquine concentrations in the dihydroartemisinin piperaquine and artemether lumefantrine recipients as a function of the calculated mg/kg dose of primaquine and age.
Fig. 3
Fig. 3
Median oral clearance of primaquine in L/h as a function of age, from 6 months to 11 years, and adjusted for body weight. Spearman rho correlation coefficients were 0.97 (p < 0.0001) and −0.37 (p < 0.0001). a. Clearance b. Clearance adjusted for body weight.
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