title: Pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and KAE609 in a murine malaria model.
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 (R2=0.97 and 0.95, respectively) but less so for the maximum concentration of drug in serum (Cmax)/TRE ratio (R2=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.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore suresh.b_lakshminarayana@novartis.com francesca.blasco@novartis.com.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Freymond
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Weber
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Anne
authors.initials: A
authors.lastname: Goh
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore suresh.b_lakshminarayana@novartis.com francesca.blasco@novartis.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D008288:Malaria / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects* / Q000472:pathogenicity*
chemical_list: D000962:Antimalarials