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Antimicrobial Agents and Chemotherapy, February 2009, p. 421-427, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00576-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Statistical Model To Evaluate In Vivo Activities of Antimalarial Drugs in a Plasmodium cynomolgi-Macaque Model for Plasmodium vivax Malaria{triangledown} ,{ddagger}

Clemens H. M. Kocken,1,{dagger} Edmond J. Remarque,1,{dagger} Martin A. Dubbeld,1 Sharon Wein,2 Annemarie van der Wel,1 R. Joyce Verburgh,1 Henri J. Vial,2* and Alan W. Thomas1*

Biomedical Primate Research Centre, Department of Parasitology, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands,1 Dynamique des Interactions Membranaires Normale et Pathologiques, CNRS UMR 5235, cc107, Université Montpellier II, Place Eugene Bataillon, 34095 Montpellier, France2

Received 2 May 2008/ Returned for modification 6 June 2008/ Accepted 7 November 2008

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.

* Corresponding author. Mailing address for A. W. Thomas: Biomedical Primate Research Centre, Department of Parasitology, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands. Phone: 31 15 284 2538. Fax: 31 15 284 2601. E-mail: thomas{at}bprc.nl. Mailing address for H. J. Vial: Dynamique des Interactions Membranaires Normale et Pathologiques, CNRS UMR 5235, cc107, Université Montpellier II, Place Eugene Bataillon, 34095 Montpellier, France. Phone: 33 46714 3745. Fax: 33 46714 4286. E-mail: vial{at}univ-montp2.fr

{triangledown} Published ahead of print on 17 November 2008.

{ddagger} Supplemental material for this article may be found at http://aac.asm.org/.

{dagger} C.H.M.K. and E.J.R. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, February 2009, p. 421-427, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00576-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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