Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria
<p><strong>Background:</strong> 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).</p> <p><strong>Methods:...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2023
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| _version_ | 1797111493132550144 |
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| author | Mukaka, M Onyamboko, MA 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, DK Ndjowo, PO Basara, BB Bongo, GS Okalebo, CB Abongo, G Uyoga, S Williams, TN Taya, C Dhorda, M Dondorp, AM Waithira, N Imwong, M Maitland, K Fanello, C Day, NPJ Tarning, J White, NJ Taylor, WRJ |
| author_facet | Mukaka, M Onyamboko, MA 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, DK Ndjowo, PO Basara, BB Bongo, GS Okalebo, CB Abongo, G Uyoga, S Williams, TN Taya, C Dhorda, M Dondorp, AM Waithira, N Imwong, M Maitland, K Fanello, C Day, NPJ Tarning, J White, NJ Taylor, WRJ |
| author_sort | Mukaka, M |
| collection | OXFORD |
| description | <p><strong>Background:</strong> 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).</p>
<p><strong>Methods:</strong> 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.</p>
<p><strong>Findings:</strong> 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.</p>
<p><strong>Interpretation:</strong> 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.</p>
<p><strong>Funding:</strong> 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.</p> |
| first_indexed | 2024-03-07T08:09:42Z |
| format | Journal article |
| id | oxford-uuid:7be62cd3-94bf-40e4-adef-355d0e1df2fd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:09:42Z |
| publishDate | 2023 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:7be62cd3-94bf-40e4-adef-355d0e1df2fd2023-11-21T12:36:59ZPharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malariaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7be62cd3-94bf-40e4-adef-355d0e1df2fdEnglishSymplectic ElementsElsevier2023Mukaka, MOnyamboko, MAOlupot-Olupot, PPeerawaranun, PSuwannasin, KPagornrat, WKouhathong, JMadmanee, WWere, WNamayanja, COnyas, PTitin, HBaseke, JMuhindo, RKayembe, DKNdjowo, POBasara, BBBongo, GSOkalebo, CBAbongo, GUyoga, SWilliams, TNTaya, CDhorda, MDondorp, AMWaithira, NImwong, MMaitland, KFanello, CDay, NPJTarning, JWhite, NJTaylor, WRJ<p><strong>Background:</strong> 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).</p> <p><strong>Methods:</strong> 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.</p> <p><strong>Findings:</strong> 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.</p> <p><strong>Interpretation:</strong> 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.</p> <p><strong>Funding:</strong> 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.</p> |
| spellingShingle | Mukaka, M Onyamboko, MA 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, DK Ndjowo, PO Basara, BB Bongo, GS Okalebo, CB Abongo, G Uyoga, S Williams, TN Taya, C Dhorda, M Dondorp, AM Waithira, N Imwong, M Maitland, K Fanello, C Day, NPJ Tarning, J White, NJ Taylor, WRJ 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 |
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