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Review 3: "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 3: "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 One participant was withdrawn without receiving pyronaridine.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:

The authors suggest a new model of PK/PD for estimating the anti-malarial activity of pyronaridine (Pyr) in human volunteers infected by Plasmodium falciparum. There are two basic deficiencies in the research: a. the number of individuals in each experimental group is very limited, too low for drawing decisive conclusions except for the known fact that Pyr has an anti-plasmodial effect; b. The authors suggest that their model may further advance research relating to the use of Pyr in drug combinations. However, following previous extensive research, Pyr (in a drug combination) has been already approved for malaria therapy since 1981.

Overall and despite using accurate experimental methods, there is no justification for publishing the MS.


Specific comments

Introduction

  • Lines 46-57. The introduction contains a standard description of the necessity of developing new anti-malarial drugs. It may be significantly shortened.

  • Lines 58-88. Why deal with Pyr which is an old drug that has been heavily investigated (249 results in PubMed, October 16, 2023) and approved for human use?

  • Lines 58-60. “Pyronaridine is active against various drug resistant strains of P. falciparum (Croft et al. 2012)”. The same reference also emphasizes parasite resistance to Pyr!

  • Lines 70-71. The official recommended concentration of Pyr in Pyramax is 720 mg/240 mg artesunate daily for three consequent days. The authors used different reduced concentrations and schedule in their experiments though there was a group of one patient who received (in a schedule different from the other experimental groups) a dose of 720 mg. The authors should have used the recommended Pyr concentration (with and without the artesunate) in addition to altered ones.

Methods

  • Lines 105-107. Four participants in an experimental group that includes candidates of different age, weight, sex and race- this is not experimentally reliable. Does the number of participants allow accurate statistical calculations?

  • Lines 146-149. “Data points where gametocytes exceed 10% of the total parasitemia were removed from the data set” because “the count of gametocytes is not precise enough”. Following this statement any discussion concerning gametocytes should not be included.

Results

  • Table 1. The results of in vivo experiments (especially following oral treatment) are influenced by sporadic events (like the nutrition in the day of treatment); this is besides the basic differences between the individual volunteers. Consequently, the insufficient selected (x1.44) difference between the used Pyr concentrations may not lead to significant results. 

  • Figure 2. If “the horizonal line indicates the lower limit of quantitation of the assay” how come that there are indications below the dotted line? R 102 should not be included due to the use of different experimental procedure/condition regarding this person.

Discussion

  • Lines 273-275. Gametocytemia is a general phenomenon following treatment with drugs that affect asexual forms of the parasite, Pyr is not an exception.

  • Lines 279-280.  These lines are redundant. Any PK/PD characterization necessitates in vivo trials.

  • Lines 280-281. These lines are redundant because such investigations are constantly ongoing.

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