ArticleAntimicrobial agents and chemotherapy2015
Pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and KAE609 in a murine malaria model.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 17 citations in OpenAlex.
- Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.Antimicrobial agents and chemotherapy · 2017Trial
- Dose-fractionation studies of aAntimicrobial agents and chemotherapy · 2024Article
- Integrating Pharmacokinetic-Pharmacodynamic Modeling and Physiologically Based Pharmacokinetic Modeling to Optimize Human Dose Predictions for Plasmodium falciparum Malaria: a Chloroquine Case Study.Antimicrobial agents and chemotherapy · 2023Article
- Defining the Antimalarial Activity of Cipargamin in Healthy Volunteers Experimentally Infected with Blood-Stage Plasmodium falciparum.Antimicrobial agents and chemotherapy · 2021Article
- Investigating Sulfoxide-to-Sulfone Conversion as a Prodrug Strategy for a Phosphatidylinositol 4-Kinase Inhibitor in a Humanized Mouse Model of Malaria.Antimicrobial agents and chemotherapy · 2018Article
- Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.PLoS medicine · 2016Article
- Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor.Scientific reports · 2016Article
- Na+ Influx Induced by New Antimalarials Causes Rapid Alterations in the Cholesterol Content and Morphology of Plasmodium falciparum.PLoS pathogens · 2016Article
- The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs.International journal for parasitology. Drugs and drug resistance · 2015Review
- Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery.Molecules (Basel, Switzerland) · 2015Review
- Malaria medicines: a glass half full?Nature reviews. Drug discovery · 2015Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
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.
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