Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development

Scientific Reports
Lydia BurgertMelissa A Penny

Abstract

Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacio...Continue Reading

References

Jul 1, 1997·Antimicrobial Agents and Chemotherapy·N J White
Mar 19, 2002·Antimicrobial Agents and Chemotherapy·Shusuke NakazawaHiroji Kanbara
Aug 20, 2002·European Journal of Clinical Pharmacology·Ulrika S H SvenssonMichael Ashton
Oct 16, 2002·Trends in Parasitology·Nicholas J White
Nov 20, 2004·Transactions of the Royal Society of Tropical Medicine and Hygiene·Mita M ThaparAnders Björkman
Mar 8, 2007·Blood·Abigail A LamikanraDavid J Roberts
Nov 13, 2008·Infection and Immunity·Julia K NunesDyann F Wirth
Feb 4, 2011·Malaria Journal·Jean LanghornePatrick Duffy
Feb 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Susan A CharmanJonathan L Vennerstrom
Sep 24, 2011·Malaria Journal·N J White
Sep 28, 2012·Proceedings. Biological Sciences·Petra SchneiderSarah E Reece
Nov 14, 2012·Antimicrobial Agents and Chemotherapy·Kashyap PatelCarl M Kirkpatrick
Jun 25, 2013·Parasitology·María Belén Jiménez-DíazIñigo Angulo-Barturen
Jul 5, 2013·PloS One·María Belén Jiménez-DíazIñigo Angulo-Barturen
Nov 13, 2013·Nature Reviews. Microbiology·Erika L FlanneryElizabeth A Winzeler
Apr 30, 2014·The Journal of Antimicrobial Chemotherapy·Kashyap PatelCarl M Kirkpatrick
May 13, 2015·Antimicrobial Agents and Chemotherapy·Louise MarquartJames S McCarthy
May 23, 2015·Nature Reviews. Drug Discovery·Timothy N C WellsWesley C Van Voorhis
Jul 22, 2015·Antimicrobial Agents and Chemotherapy·Mateusz M PlucinskiVenkatachalam Udhayakumar
Apr 6, 2016·Antimicrobial Agents and Chemotherapy·James S McCarthyJörg J Möhrle
Oct 30, 2016·Trends in Parasitology·Hannah C SlaterAzra C Ghani
Jan 5, 2017·Journal of Medicinal Chemistry·Yuxiang DongJonathan L Vennerstrom
Jan 15, 2017·Malaria Journal·Jeremy N BurrowsTimothy N C Wells
Apr 28, 2017·Science Translational Medicine·Tanya PaquetKelly Chibale
Jul 5, 2017·Proceedings of the National Academy of Sciences of the United States of America·David S KhouryMiles P Davenport
Aug 5, 2017·Nature Reviews. Disease Primers·Margaret A PhillipsTimothy N C Wells
Aug 22, 2018·Immunological Reviews·David S KhouryMiles P Davenport

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Citations

Jul 2, 2020·British Journal of Pharmacology·Ana Carolina Moreira SouzaSylvain Richard
Sep 30, 2020·Current Pathobiology Reports·Adrianne L JennerMorgan Craig
Feb 2, 2021·Clinical Pharmacology and Therapeutics·Lena E Friberg
Feb 3, 2021·Antimicrobial Agents and Chemotherapy·Lydia BurgertMelissa A Penny
Jun 29, 2021·Journal of Computer-aided Molecular Design·Olivia TeixeiraMarcelo Santos Castilho

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