Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected with<i>Plasmodium falciparum</i>

Barber, Bridget E.; Abd-Rahman, Azrin N; Webster, Rebecca; Potter, Adam J; Llewellyn, Stacey; Marquart, Louise; Sahai, Nischal; Leelasena, Indika; Birrell, Geoffrey W; Edstein, Michael D.; Shanks, G. Dennis; Wesche, David; Moehrle, Joerg J.; McCarthy, James S.

doi:10.1101/2022.11.21.22282610

Cited by 2 publications

(1 citation statement)

References 34 publications

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“…When considering new compounds that could be either combined with artesunate or developed into novel drug combinations, there are several molecules in the current development pipeline with characteristics indicating potential for the treatment of severe malaria (Table 2, Fig. 4) [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90]. The most advanced candidate is cipargamin, a novel spiroindolone anti-malarial targeting PfATP4 currently in phase 2 development by Novartis [56,[91][92][93].…”

Section: Severe Malaria Pipelinementioning

confidence: 99%

Defining the next generation of severe malaria treatment: a target product profile

Achan,

Barry,

Leroy

et al. 2024

Malar J

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Background Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa. Hence, new treatments for severe malaria are needed, and it is prudent to define their characteristics now. This manuscript focuses on the target product profile (TPP) for new treatments for severe malaria. It also highlights preparedness when considering ways of protecting the utility of artemisinin-based therapies. Target product profile Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings. Conclusion Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease.

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Section: Severe Malaria Pipelinementioning

confidence: 99%

Defining the next generation of severe malaria treatment: a target product profile

Achan,

Barry,

Leroy

et al. 2024

Malar J

View full text Add to dashboard Cite

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Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected withPlasmodium falciparum

Barber,

Webster,

Potter

et al. 2023

Preprint

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Although pyronaridine has been used to successfully treat malaria for many years, its antimalarial activity in humans has not been completely characterized. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in healthy malaria naive adults. Volunteers were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0 and different single oral doses of pyronaridine were administered on day 8. Parasitemia, and concentrations of pyronaridine in whole blood were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47+/-2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n=4), 540 mg (n=4), or 720 mg (n=1) pyronaridine. One participant was withdrawn without receiving pyronaridine. Time to maximum pyronaridine concentration after dosing was 1-2 hours and the elimination half-life was 8-9 days. A parasite clearance half-life of approximately 5 hours was calculated for all dose levels. Parasite regrowth occurred after dosing with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters of pyronaridine including the minimum inhibitory concentration (MIC: 5.5 ng/mL) and minimum parasiticidal concentration that leads to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the final PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.

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Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected withPlasmodium falciparum

Cited by 2 publications

References 34 publications

Defining the next generation of severe malaria treatment: a target product profile

Defining the next generation of severe malaria treatment: a target product profile

Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected withPlasmodium falciparum

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