title: Intrahost modeling of artemisinin resistance in Plasmodium falciparum.
abstract: Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log(10) scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Rajthevee, Bangkok 10400, Thailand. sompob@tropmedres.ac
authors.forename: Sompob
authors.initials: S
authors.lastname: Saralamba
authors.forename: Wirichada
authors.initials: W
authors.lastname: Pan-Ngum
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maude
authors.forename: Sue J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Niklas
authors.initials: N
authors.lastname: Lindegårdh
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: White
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077332:Artesunate; D002160:Cambodia / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology*; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate