title: Statistical model to evaluate in vivo activities of antimalarial drugs in a Plasmodium cynomolgi-macaque model for Plasmodium vivax malaria.
abstract: Preclinical animal models informing antimalarial drug development are scarce. We have used asexual erythrocytic Plasmodium cynomolgi infections of rhesus macaques to model Plasmodium vivax during preclinical development of compounds targeting parasite phospholipid synthesis. Using this malaria model, we accumulated data confirming highly reproducible infection patterns, with self-curing parasite peaks reproducibly preceding recrudescence peaks. We applied nonlinear mixed-effect (NLME) models, estimating treatment effects in three drug studies: G25 (injected) and the bisthiazolium prodrugs TE4gt and TE3 (oral). All compounds fully cured P. cynomolgi-infected macaques, with significant effects on parasitemia height and time of peak. Although all three TE3 doses tested were fully curative, NLME models discriminated dose-dependent differential pharmacological antimalarial activity. By applying NLME modeling treatment effects are readily quantified. Such drug development studies are more informative and contribute to reduction and refinement in animal experimentation.
authors.affiliation: Biomedical Primate Research Centre, Department of Parasitology, GH Rijswijk, The Netherlands.
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Remarque
authors.forename: Martin A
authors.initials: MA
authors.lastname: Dubbeld
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Annemarie
authors.initials: A
authors.lastname: van der Wel
authors.forename: R Joyce
authors.initials: RJ
authors.lastname: Verburgh
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
authors.forename: Alan W
authors.initials: AW
authors.lastname: Thomas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D015233:Models, Statistical; D016789:Plasmodium cynomolgi; D011355:Prodrugs / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use
chemical_list: C448986:1,16-hexadecamethylenebis(N-methylpyrrolidinyl); D000962:Antimalarials; D011355:Prodrugs; D011759:Pyrrolidines