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Pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and KAE609 in a murine malaria model

Lakshminarayana, Suresh B. and Freymond, Céline and Fischli, Christoph and Yu, Jing and Weber, Sebastian and Goh, Anne and Yeung, Bryan K. S. and Ho, Paul C. and Dartois, Véronique and Diagana, Thierry T. and Rottmann, Matthias and Blasco, Francesca. (2015) Pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and KAE609 in a murine malaria model. Antimicrobial agents and chemotherapy, Vol. 59, H. 2. pp. 1200-1210.

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Official URL: http://edoc.unibas.ch/dok/A6348549

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Abstract

Limited information is available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters driving the efficacy of antimalarial drugs. Our objective in this study was to determine dose-response relationships of a panel of related spiroindolone analogs and identify the PK-PD index that correlates best with the efficacy of KAE609, a selected class representative. The dose-response efficacy studies were conducted in the Plasmodium berghei murine malaria model, and the relationship between dose and efficacy (i.e., reduction in parasitemia) was examined. All spiroindolone analogs studied displayed a maximum reduction in parasitemia, with 90% effective dose (ED90) values ranging between 6 and 38 mg/kg of body weight. Further, dose fractionation studies were conducted for KAE609, and the relationship between PK-PD indices and efficacy was analyzed. The PK-PD indices were calculated using the in vitro potency against P. berghei (2× the 99% inhibitory concentration [IC99]) as a threshold (TRE). The percentage of the time in which KAE609 plasma concentrations remained at <2× the IC99 within 48 h (%T<TRE) and the area under the concentration-time curve from 0 to 48 h (AUC0-48)/TRE ratio correlated well with parasite reduction (R(2) = 0.97 and 0.95, respectively) but less so for the maximum concentration of drug in serum (Cmax)/TRE ratio (R(2) = 0.88). The present results suggest that for KAE609 and, supposedly, for its analogs, the dosing regimens covering a T<TRE of 100%, AUC0-48/TRE ratio of 587, and a Cmax/TRE ratio of 30 are likely to result in the maximum reduction in parasitemia in the P. berghei malaria mouse model. This information could be used to prioritize analogs within the same class of compounds and contribute to the design of efficacy studies, thereby facilitating early drug discovery and lead optimization programs.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:12
Deposited On:10 Apr 2015 09:12

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