Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose–Efficacy Modeling
| Autor: | Thomas Weller, Jeremy N. Burrows, David A. Fidock, Sergio Wittlin, Rintis Noviyanti, Robert W. Sauerwein, Grennady Wirjanata, Robert E. Sinden, María Santos Martínez, Christoph Binkert, Christopher Snyder, Nina F. Gnädig, Stephan Buchmann, Ruben de Kanter, Andrea Ruecker, Christoph Fischli, Michael J. Delves, Joerg J. Moehrle, Iñigo Angulo-Barturen, Koen J. Dechering, Christian Scheurer, Francisco Javier Gamo Benito, Solange Meyer, Laura M. Sanz, Christoph Boss, Sarah Schleiferboeck, Martine Clozel, Sonja Ewerling, Caroline L. Ng, Reto Brun, María Belén Jiménez-Díaz, Didier Leroy, Jutta Marfurt, Santiago Ferrer, Walter Fischli, Amélie Le Bihan, Judith Straimer, Bibia Heidmann, Ric N. Price, Ralf Brunner |
|---|---|
| Přispěvatelé: | Medicines for Malaria Venture |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmodium Physiology Plasmodium berghei Plasmodium vivax lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Pharmacology Gametocytes Piperazines Mice Animal Cells Mice Inbred NOD Medicine and Health Sciences Artemisinin GeneralLiterature_REFERENCE(e.g. dictionaries encyclopedias glossaries) Protozoans biology Pharmaceutics Malarial Parasites Drugs General Medicine 11 Medical And Health Sciences Animal Models Hematology Artemisinins 3. Good health Body Fluids Blood Medicine Female Cellular Types Anatomy Multidrug Resistance-Associated Proteins medicine.drug Research Article Combination therapy 030106 microbiology Plasmodium falciparum Cmax Mouse Models Microbial Sensitivity Tests Research and Analysis Methods 03 medical and health sciences Antimalarials Model Organisms Dose Prediction Methods General & Internal Medicine Parasite Groups parasitic diseases medicine Gametocyte Parasitic Diseases Animals Humans Acrylamides Dose-Response Relationship Drug Organisms Biology and Life Sciences Cell Biology biology.organism_classification Tropical Diseases Parasitic Protozoans Malaria Germ Cells Pharmacodynamics Parasitology Apicomplexa |
| Zdroj: | Plos Medicine, 13, e1002138 Plos Medicine, 13, 10, pp. e1002138 PLoS Medicine PLoS Medicine, Vol 13, Iss 10, p e1002138 (2016) |
| ISSN: | 1549-1277 |
| Popis: | Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose–efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study. Sergio Wittlin and colleagues report in vivo and in vitro modelling of antimalarial activity and dose-efficacy of a new drug candidate. Author Summary Why Was This Study Done? The limited diversity of chemical mode of action in the global portfolio of marketed antimalarials along with recently observed artemisinin resistance that threatens the current first-line treatment highlights the urgent need for development of new antimalarials. In accordance with target product profiles defined by the Medicines for Malaria Venture ([MMV]; www.mmv.org), a new model of not-for-profit public–private partnership providing guidance to the development of new drugs, ACT-451840, a new chemical class of potent compounds with a novel mode of action, was selected for early development. This manuscript integrates a number of studies performed to characterize preclinically ACT-451840 and illustrates the new antimalarial drug development paradigm. What Did the Researchers Do and Find? This study used in vitro models to investigate compound activity on sexual and asexual blood stages and a mouse model to study the human parasite P. falciparum in vivo. While being fully active against artemisinin-resistant strains, ACT-451840 shares many of the favorable properties of artemisinins like its fast onset of action, activity against all asexual blood stage forms, and a PRR of >4 log per parasite cycle. Pharmacodynamic properties of ACT-451840 were interpreted in two mouse models of malaria with respect to the pharmacokinetic properties, with the objective to establish the portable PK/PD parameters to estimate efficacious exposure. What Do These Findings Mean? Modeling the dose–efficacy relationship of ACT-451840 supported prediction of the human efficacious exposure and therefore laid the groundwork for the new clinical development phases. Confirmed in an experimental human malaria infection model, the properties of ACT-451840, including its fast action observed in in vitro and in vivo models and its transmission-blocking activity, suggest this compound may be able to replace the artemisinin component in artemisinin-based combination therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|