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.
Highlights
Novartis Institute for Tropical Diseases, Singaporea; Swiss Tropical and Public Health Institute, Basel, Switzerlandb; University of Basel, Basel, Switzerlandc; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USAd; Novartis Pharma, Basel, Switzerlande; Department of Pharmacy, National University of Singapore, Singaporef
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
PK-PD relationships have been established for chloroquine and artesunate [27]
Summary
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. Numerous clinical pharmacokinetic and therapeutic drug monitoring programs have been launched to assess the adequacy of drug doses and to model dose response in uncomplicated and severe malaria [18,19,20] Quantitative pharmacodynamic readouts, such as parasitemia, parasite clearance rates, and parasite clearance time, are used to assess the parasitological response to treatment in relation to clinical outcome [21, 22]. Based on these advances and a better definition of clinical and parasito-
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