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Review 1: "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
Review 1: "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 One participant was withdrawn without receiving pyronaridine.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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

This study will provide data to inform potential new pyronaridine-based antimalarial combination therapies. This would be another treatment option to cure patients with malaria and reduce disease burden. 

The authors of this manuscript used a population approach to model PK, and PD-- parasite killing effect of an anti-malaria drug, pyronaridine, in healthy naïve malaria subjects. This study was very interesting, and generated some key PK metrics (like MIC, MPC90) that link to PD effect. The data is useful to understand PK-PD relationship of pyronaridine and could inform dosage regimen for pyronaridine-based new anti-malaria combination therapy.  The reviewer has a few comments on main claims, not on technical details.  

  1. The author used sequential approach to conduct PK-PD analysis. The overall analysis approach and procedure is appropriate.

  2. Non-compartmental PK analysis indicated pyronaridine displayed predictable PK properties (roughly linear PK in both Cmax and AUC), which will decrease uncertainty in PK modelling analysis.

  3. First, a population PK for pyronaridine was established and evaluated. The PK model was quite straightway (2 compartment model with zero-order absorption). Although the model evaluation was not enough (no goodness of fit plot, no VPC plot, no parameter uncertainties), the individual plots showed good agreement between model individual predicted PK data and observed PK data, which gave some extent of confidence for model prediction.

  4. Then, the individual PK parameters were link to malaria parasitemia killing effect (methodology is not well described, suppose it was model predicted individual concentration to drive PD). The model included parasite net growth rate. Eventually, two key PK matrices (MIC, MPC90) were derived. The PK-PD model was not well evaluated (no goodness of fit plot, no VPC plot), overall, the individual prediction was able to capture observed parasitemia data, particular in those with parasite re-growth, allowing to estimate of MIC and MPC90.

  5. The main finding supports (MIC) the current Pyramax (720 mg pyronaridine/ 240 mg artesunate daily for three consecutive days) dosing regimen. Pyronaridine 720 mg is the clinical cure dose.

  6. Small patient number will have impact on key parameter estimates, particular for variability. The findings need to refine based on future clinical data.

  7. No main safety finding in all healthy subjects, but only 1 subject in the highest 720 mg group. 

  8. Although this manuscript has many technical issues to be clarified and improved, the finding of this analysis was still potential informative. It could provide insight to inform new anti-malaria therapy. 

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