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Discussion Amongst Reviewers: "Characterizing the Blood Stage Antimalarial Activity of Pyronaridine in Healthy Volunteers Experimentally Infected with Plasmodium Falciparum"

Because the reviewers had differing opinions of the robustness of the manuscript, we gave them an opportunity to discuss the reviews amongst themselves, as attached detailed in the supplement "Discussion Amongst Reviews". 

Published onDec 14, 2023
Discussion Amongst Reviewers: "Characterizing the Blood Stage Antimalarial Activity of Pyronaridine in Healthy Volunteers Experimentally Infected with Plasmodium Falciparum"
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Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum
Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum
Description

ABSTRACT 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 naïve 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 One participant was withdrawn without receiving pyronaridine.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.

Comments from Reviewer 1 [Junjie Ding]:

Reviewer 2 [Thanaporn Wattanakul] recognized the value of PK-PD analysis of pyronaridine in antimalarial therapy. Reviewer 3 [Anonymous] pointed out the key deficiencies of this paper. My view is that the dose levels used in this human study are roughly appropriate to cover the entire PK-PD curve regarding the purpose (i.e, PK-PD relationship). One dose level, such as clinical dose, does not fit that purpose.

Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.  Pyronaridine is potentially a partner drug in new ACT combinations. Despite a long history, there is only limited knowledge of the clinical PK and PD of pyronaridine. I’d like to say the PK-PD data will still be useful to address the data gap and justify the dose for current ACT and inform dose for new combinations, although the data might not be sufficient enough due to limited patient numbers. 

Comments from Reviewer 2 [Thanaporn Wattanakul]:

Reviewer 1 [Junjie Ding] acknowledge the benefit of the study regarding the crucial PK/PD information of pyronaridine. I also agreed with their assessment. Although pyronaridine is an old drug, the information like MIC or MPC90 in vivo is limited. In my point of view, this information could aid the rational dose selection in the new combination therapy.

Reviewer 1 [Junjie Ding] & 3 [Anonymous] highlighted a limitation concerning the limited number of participants included in the study, suggesting that this could lead to less reliable parameter estimates due to substantial variability. I agree with their observation, emphasizing the necessity for a future study with an increased number of participants to enhance the robustness of the findings.

In general, enhancing this work could be achieved by providing additional information on the processes involved in model development and presenting the results of model evaluations, including measures of goodness-of-fits and visual predictive checks.

Comments from Reviewer 3 [Anonymous]:

Both Reviewer 1 [Junjie Ding] and 2 [Thanaporn Wattanakul] emphasize the benefit of a new model of PK/PD. I found some weaknesses in the MS: mainly, the effect of pyronaridine was examined in a very limited number of malaria patients, the examined drug is an old one to which resistance has already emerged and the treatment was performed by using a non-recommended dose. Taking in account  some additional comments (see in my complete review) I cannot recommend publication

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