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Review 2: "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 2: "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 One participant was withdrawn without receiving pyronaridine.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:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The study characterized pyronaridine's pharmacokinetic (PK)/pharmacodynamic (PD) relationship in malaria-naïve healthy adults. Key efficacy parameters, such as the minimum inhibitory concentration (MIC) of 5.5 ng/mL and the minimum parasiticidal concentration leading to 90% of the maximum effect (MPC90) of 8 ng/mL, were derived from the final PK/PD model, which could inform partner drug selection and dosing for pyronaridine in new antimalarial combination therapies. 

This work possesses several strengths. The application of the induced blood stage malaria (IBSM) model within the volunteer infection study (VIS) facilitates the exploration of parasite dynamics both before and after antimalarial drug treatment. Notably, the availability of pharmacokinetic (PK)/pharmacodynamic (PD) data for a single antimalarial drug is a rarity, given that these drugs are typically prescribed as combination therapies. Such data are essential for characterizing the individual drug's efficacy. Therefore, the in vivo efficacy parameters of pyronaridine highlighted in this study offer crucial insights for optimizing dosages in the development of new antimalarial combination therapies.

This study received ethical approval from the QIMR Berghofer Human Research Ethics Committee, and all participants provided written informed consent. The authors also comprehensively detailed the inclusion and exclusion criteria in the supplementary. The curative treatments for sexual and asexual parasites, i.e., primaquine and artemether-lumefantrine, were clearly defined. The authors also provided a detailed description of the participant that was not included in the PK/PD analysis.

While the study procedures, including the VIS using the IBSM model, and the PK/PD analysis, were well-described, it would be beneficial to provide a more elaborate explanation of how the PK/PD analysis was conducted. This could include sharing the equations used to describe the relationship between pyronaridine concentration and its parasite-killing activity, as well as the equation employed to estimate the parasite growth rate. Such details would enhance the understanding of the developed model, particularly for those less familiar with this type of work.

The authors clearly reported the estimated PK parameters and PK/PD parameters. Key findings revealed that parasitemia progression was consistent among participants following intravenous inoculation from day 0 to day 8. Pyronaridine demonstrated a dose-related increase in exposure, with a time to maximum concentration of 1-2 hours and an elimination half-life of 8-9 days. The parasite clearance half-life was approximately 5 hours across all dose groups. 

The authors discussed differences in the estimated pharmacokinetic parameters from this study compared to those from other studies, both in healthy individuals and malaria patients. It was discussed that these variations could be attributed to the limited number of participants in the current study. However, these differences do not affect the estimated PK/PD relationship since the data was collected from the same individuals. One additional point that may be worth discussing is the impact of the parasite strain used in the IBSM model (Plasmodium falciparum 3D7), which differs from the strain in clinical infections. This difference may influence the estimated killing activity of pyronaridine. 

Furthermore, the authors mentioned an ongoing phase 2a study of pyronaridine in combination with a new antimalarial candidate (M5717), which has shown additive parasitological activity in a preclinical study. The availability of data from the IBSM model for both pyronaridine and M5717 is a valuable resource for evaluating the dosing regimen of this new antimalarial combination therapy. This could have a substantial impact on future antimalarial treatment programs. The manuscript was well-written, with minor improvements suggested, such as presenting figures and tables in chronological order to enhance the reader's comprehension. 

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