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As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug, and a third drug with …

Authors: Daniel J. Watson, Lizahn Laing, Liezl Gibhard, Ho Ning Wong, Richard K. Haynes, Lubbe Wiesner

Date Published: 16th Jul 2021

Publication Type: Journal

DOI: 10.1128/AAC.00990-21

Citation: Antimicrob Agents Chemother 65(8),e00990-21

Created: 9th Jan 2023 at 09:19, Last updated: 9th Jan 2023 at 09:26

A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

Abstract Background MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics, …

Authors: James S McCarthy, Cristina Donini, Stephan Chalon, John Woodford, Louise Marquart, Katharine A Collins, Felix D Rozenberg, David A Fidock, Mohammed H Cherkaoui-Rbati, Nathalie Gobeau, Jörg J Möhrle

Date Published: 15th Nov 2020

Publication Type: Journal

DOI: 10.1093/cid/ciaa368

Citation: Clinical Infectious Diseases 71(10):e657-e664

Created: 9th Jan 2023 at 09:30, Last updated: 9th Jan 2023 at 09:30

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined …

Authors: Phumla Sinxadi, Cristina Donini, Hilary Johnstone, Grant Langdon, Lubbe Wiesner, Elizabeth Allen, Stephan Duparc, Stephan Chalon, James S. McCarthy, Ulrike Lorch, Kelly Chibale, Jörg Möhrle, Karen I. Barnes

Date Published: 24th Mar 2020

Publication Type: Journal

DOI: 10.1128/AAC.01896-19

Citation: Antimicrob Agents Chemother 64(4),e01896-19

Created: 9th Jan 2023 at 09:45, Last updated: 9th Jan 2023 at 09:46

Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract

Not specified

Authors: Tianming Dai, Weifan Jiang, Zizheng Guo, Yanxiang Xie, Renke Dai

Date Published: 2019

Publication Type: Journal

DOI: 10.1016/j.jpba.2018.09.024

Citation: Journal of Pharmaceutical and Biomedical Analysis 162:140-148

Created: 9th Jan 2023 at 09:28, Last updated: 9th Jan 2023 at 09:29

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

MMV390048, a member of a new class of inhibitors of the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis. …

Authors: Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P. Henrich, Tara S. Abraham, Marcus C. S. Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M. Blagborough, Sara E. Zakutansky, Anne-Marie Zeeman, Karen L. White, David M. Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J. Dechering, Robert W. Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J. Witty, Kennan C. Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M. Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A. Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K. Hanson, Gerard Drewes, Clemens H. M. Kocken, Michael J. Delves, Didier Leroy, David A. Fidock, David Waterson, Leslie J. Street, Kelly Chibale

Date Published: 26th Apr 2017

Publication Type: Journal

DOI: 10.1126/scitranslmed.aad9735

Citation: Sci. Transl. Med. 9(387),eaad9735

Created: 9th Jan 2023 at 09:35

Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites

Abstract (Expand)

Abstract Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of …of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.

Authors: Carrie A Morris, Stephan Duparc, Isabelle Borghini-Fuhrer, Donald Jung, Chang-Sik Shin, Lawrence Fleckenstein

Date Published: 1st Dec 2011

Publication Type: Journal

DOI: 10.1186/1475-2875-10-263

Citation: Malar J 10(1),263

Created: 9th Jan 2023 at 09:32, Last updated: 9th Jan 2023 at 09:32

Pharmacokinetics of Artemisinin-Type Compounds

WP 4: Evaluation of drug activity against multiple life cycle stages of malaria parasites