Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

Senarathna, S M D K Ganga; Batty, Kevin T.

doi:10.1128/aac.02538-14

Cited by 8 publications

(4 citation statements)

References 141 publications

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“…16 ), which was higher than typical ranges for this parameter (0.67–0.75) 38 . Consequently, a maximum life-span potential (MLP) correction was implemented resulting in an estimated total clearance of 1.8 ml/min/kg 39 . Second, human clearance was estimated from in vitro hepatocyte clearance assays.…”

Section: Resultsmentioning

confidence: 99%

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

et al. 2022

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Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.

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Section: Resultsmentioning

confidence: 99%

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

et al. 2022

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“…[8,9]. Guidelines published by the WHO on how to dose antimalarial drugs in children are also based on body weight [10]. However, children under the age of 5 years are not small adults, and their physiology, liver enzyme maturation, and serum proteins have not fully developed and may, therefore, significantly influence the pharmacokinetics of drugs and how they behave in the body.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Allometric scaling is an experimental methodology often used for scaling between animal species, where the conversion of dose is based on the surface area of the body or on the weight associated with the metabolic rate [12]. The usual purposes of interspecies scaling involve predicting the dose in humans as a result of extrapolating from preclinical experiments [10].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach

et al. 2023

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Most of the individuals who die of malaria in sub–Saharan Africa are children. It is, therefore, important for this age group to have access to the right treatment and correct dose. Artemether—lumefantrine is one of the fixed dose combination therapies that was approved by the World Health Organization to treat malaria. However, the current recommended dose has been reported to cause underexposure or overexposure in some children. The aim of this article was, therefore, to estimate the doses that can mimic adult exposure. The availability of more and reliable pharmacokinetic data is essential to accurately estimate appropriate dosage regimens. The doses in this study were estimated using the physiological information from children and some pharmacokinetic data from adults due to the lack of pediatric pharmacokinetic data in the literature. Depending on the approach that was used to calculate the dose, the results showed that some children were underexposed, and others were overexposed. This can lead to treatment failure, toxicity, and even death. Therefore, when designing a dosage regimen, it is important to know and include the distinctions in physiology at various phases of development that influence the pharmacokinetics of various drugs in order to estimate the dose in young children. The physiology at each time point during the growth of a child may influence how the drug is absorbed, gets distributed, metabolized, and eliminated. From the results, there is a very clear need to conduct a clinical study to further verify if the suggested (i.e., 0.34 mg/kg for artemether and 6 mg/kg for lumefantrine) doses could be clinically efficacious.

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“…First, a clearance exponent of 0.967 was derived using simple allometry, which was higher than typical ranges for this parameter (0.67-0.75) (34). Consequently, the maximum life-span potential (MLP) correction was implemented resulting in an estimated total clearance of 1.8 ml/min/kg (35). Second, human hepatic clearance was measured at 0.51 ml/min/kg based on the in vitro hepatocyte clearance of 0.4 µl/min/10 6 cells.…”

Section: Human Pharmacokinetic Predictionsmentioning

confidence: 99%

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Vries

Barceló

et al. 2021

Preprint

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Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic-pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.

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Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

Cited by 8 publications

References 141 publications

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

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