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Pharmacokinetics-pharmacodynamics analysis of spiroindolone analogs and KAE609 in a murine malaria model

Lakshminarayana, Suresh Bangalore and Freymond, Celine and Fischli, Christoph and Yu, Jing and Weber, Sebastian and Goh, Anne and Yeung, Bryan King Sing and Ho, Paul C and Dartois, Veronique and Diagana, Thierry Tidiane and Rottmann, Matthias and Blasco, Francesca (2014) Pharmacokinetics-pharmacodynamics analysis of spiroindolone analogs and KAE609 in a murine malaria model. Antimicrobial Agents and Chemotherapy.

Abstract

Limited information is available on pharmacokinetic and pharmacodynamic (PK-PD) parameters driving the efficacy of anti-malarial drugs. Our objective was to determine dose response relationship to a panel of related spiroindolone analogs and identify the PK-PD index that best correlate with the efficacy of KAE609, a selected class representative. Dose-response efficacy studies were conducted in the P. berghei murine malaria model and the relationship between dose and efficacy was examined. All spiroindolone analogs studied displayed maximum parasitemia reduction with ED90 values ranging between 6 and 38 mg/kg. Most of the analogs provided a maximum survival of 14 to 15 days for the highest dose administered, with complete cure (i.e. >30 days survival) achieved only with KAE609. Further, dose fractionation studies were conducted for KAE609 and the relationship between PK-PD indices and efficacy (i.e. parasitemia reduction) was examined. PK-PD indices were calculated using as threshold (TRE) the in vitro potency against P. berghei (2*IC99). The percentage of the time in which KAE609 plasma concentration remained above 2*IC99 for 48 hrs (%T>TRE) and the AUC0-48/TRE correlated well with parasite reduction (R2=0.96 and 0.95, respectively) followed by the Cmax/TRE (R2=0.88). We cannot clearly differentiate between concentration and time-dependent killing for KAE609 based on this experiment. Furthermore, the present results suggest that for KAE609 a dosing regimen covering T>TRE of 100%, AUC/TRE of 600 and Cmax/TRE of 35 for an observation period of 48h is likely to result in >99% parasitemia reduction in the mouse.

Item Type: Article
Keywords: Preclinical PK-PD, antimalarials, spiroindolones
Date Deposited: 02 May 2016 23:45
Last Modified: 02 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/20720

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