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Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania

2010-11Journal article Open access
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dc.contributor.authorHietala, Sofia Friberg
dc.contributor.authorMartensson, Andreas
dc.contributor.authorNgasala, Billy
dc.contributor.authorDahlstrom, Sabina
dc.contributor.authorLindegardh, Niklas
dc.contributor.authorAnnerberg, Anna
dc.contributor.authorPremji, Zul
dc.contributor.authorFarnert, Anna
dc.contributor.authorGil, J. P.
dc.contributor.authorBjorkman, Anders
dc.contributor.authorAshton, Michael
dc.date.accessioned2018-12-07T14:57:59Z
dc.date.available2018-12-07T14:57:59Z
dc.date.issued2010-11
dc.description.abstractThe combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.
dc.description.sponsorshipSida [SWE-2005 017]; Wellcome Trust-Mahidol University [077166/Z/05/Z]; Wellcome Trust of Great Britain
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1128/AAC.00252-10
dc.identifier.issn0066-4804
dc.identifier.urihttp://hdl.handle.net/10400.1/11799
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAmerican Society for Microbiology
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectPlasmodium-Falciparum
dc.subjectHealthy-subjects
dc.subjectDose pharmacokinetics
dc.subjectAsymptomatic children
dc.subjectDynamics
dc.subjectTrial
dc.subjectArtemisinin
dc.subjectBenflumetol
dc.subjectEfficacy
dc.subjectPlasma
dc.titlePopulation pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage4788
oaire.citation.issue11
oaire.citation.startPage4780
oaire.citation.titleAntimicrobial Agents and Chemotherapy
oaire.citation.volume54
person.familyNameGil
person.givenNameJosé Pedro
person.identifier.ciencia-idD01A-B30E-BCD5
person.identifier.orcid0000-0002-6107-9379
person.identifier.scopus-author-id7201625436
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationcb728715-0e4c-4ae5-9e21-b6a8f35a8313
relation.isAuthorOfPublication.latestForDiscoverycb728715-0e4c-4ae5-9e21-b6a8f35a8313

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