N. Terranova (1), M.B Jiménez-DÃaz (2), I. Angulo-Barturen (2), P. Magni (1), O. Della Pasqua (3)
(1) Dipartimento di Ingegneria Industriale e dell’Informazione, Università degli Studi di Pavia, Pavia, Italy; (2) Malaria DPU, Medicines Discovery Development, GlaxoSmithKline, Tres Cantos, Spain; (3) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK
Objectives: In humans, severe malaria is responsible of over a million of deaths every year. The development of new antimalarial compounds and vaccines is a critical for malaria eradication. Of particular interest is the development of compounds that are effective against Plasmodium falciparum. A new murine model has been developed to assess the therapeutic efficacy of antimalarial drugs using human erythrocytes, which better reflects disease processes (i.e., protozoa clearance) in humans [1]. The objective of this investigation was to develop a PKPD model describing protozoa dynamics and drug effects following chronic administration of atovaquone.
Methods: To measure the efficacy of atovaquone against infection by Plasmodium falciparum, female humanized mice were engrafted with human erythrocytes as performed in [1] and then infected with a specific strain of this parasite. The experiment included control and active treatment groups. Blood concentrations of atovaquone were collected in treated animals .Protozoa load and fraction or infected human erythrocytes were used as pharmacodynamic endpoints. The parasite dynamics, pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of atovaquone were characterised using nonlinear mixed effects modelling (NONMEM v.7.1).
Results: The pharmacokinetics of atovaquone was described by one compartment model with first order absorption. Parasite dynamics were evaluated using a user-defined compartmental model, in which infected and non-infected erythrocyte pools are defined. Drug effect was successfully parameterised in terms of an Imax model. Preliminary results indicate that the model is able to describe experimental data, in spite of considerable variability in parasite load.
Conclusions: Model-based approaches have been applied successfully to describe drug effects in experimental models of viral infection and translate preclinical findings into therapeutic recommendations. Our exercise suggests that comparable advantages exist for the evaluation of treatment effect and recrudescence in parasitic infections. Further validation of the proposed PKPD model is still ongoing, which will demonstrate the potential generalisability of the approach.
References:
[1] M.B Jiménez-DÃaz, T. Mulet, V. Gómez, S. Viera, A. Alvarez, H. Garuti, Y. Vázquez, A. Fernández, J. Ibáňez, M. Jiménez, D. Gargallo-Viola, I.Angulo-Barturen. Quantitative Measurement of Plasmodium-Infected Erythrocytes in Murine Models of Malaria by Flow Cytometry Using Bidimensional Assessment of SYTO-16 Fluorescence, Cytometry Part A , p. 225-235, DOI: 10.1002/cyto.a.20647.
Reference: PAGE 21 (2012) Abstr 2574 [www.page-meeting.org/?abstract=2574]
Poster: Infection