Dose‐Dependent Risk of Neutropenia after 7‐Day Courses of Artesunate Monotherapy in Cambodian Patients with Acute<i>Plasmodium falciparum</i>Malaria

Bethell, Delia; Se, Youry; Lon, Chanthap; Socheat, Duong; Saunders, David; Teja‐Isavadharm, Paktiya; Khemawoot, Phisit; Sea, Darapiseth; Lin, Jessica T.; Sriwichai, Sabaithip; Kuntawungin, Worachet; Surasri, Sittidech; Lee, Sue J.; Sarim, Ses; Tyner, Stuart D.; Smith, Bryan; Fukuda, Mark M.

doi:10.1086/657402

Cited by 50 publications

(42 citation statements)

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“…Despite a lack of dose response for antimalarial activity, artesunate did produce a dose-limiting neutropenia in 5 of 28 subjects, as reported previously (6). It is unclear at this time if the effect on the neutrophil could be reduced by using higher doses over shorter periods, but given the lack of additional efficacy at higher doses, it does not appear that this strategy is likely to be effective.…”

Section: Figmentioning

confidence: 54%

“…Malaria whole-blood films for parasite density were collected by finger stick and/or venipuncture 8 times in the first 24 h (at 0, 2,4,6,8,12,18, and 24 h) and then every 6 h until 2 negative smears were obtained. Thick and thin smears were prepared with counts per 200 white blood cells (WBC) on a thick film or per 5,000 red blood cells (RBC) on a thin film with a minimum of 200 oil immersion fields examined aac.asm.org 5485 before a negative read was determined.…”

Section: Clinicalmentioning

confidence: 99%

“…Pharmacokinetic parameters were calculated using noncompartmental analysis (NCA) with PK Solutions software, after determining that there was little difference between NCA and a one-compartment model calculated using Phoenix WinNonlin version 1.3 (Pharsight Corporation). The PK parameters determined were the elimination half-life (t 1/2 ), maximum concentration in plasma by inspection (C max ), time to reach C max (T max ), the areas under the concentration-time curve (AUC) from 0 h to ϱ (AUC 0 -ϱ ), 0 to 6 h (AUC 0 -6 ), 0 to 8 h (AUC 0 -8 ), and 2 to 6 h (AUC [2][3][4][5][6] ), the mean residence time (MRT), the volume of distribution (V), and the clearance (CL). For extravascular models, the fraction of dose absorbed cannot be estimated.…”

Section: Clinicalmentioning

confidence: 99%

“…The dose was rounded up to the nearest 1/4 tablet, with quality control analysis of study drug as described previously (7). However, the high-dose cohort (6 mg/ kg) was halted due to dose-limiting neutropenia after 28 patients had been enrolled (6). Subjects were monitored for 42 days for clinical efficacy, safety, pharmacokinetic (PK) analysis, and parasite molecular and in vitro drug resistance phenotype characterization.…”

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confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Saunders

Khemawoot

Vanachayangkul

et al. 2012

Antimicrob Agents Chemother

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h Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated Plasmodium falciparum malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither in vitro parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships. O ral artesunate (AS) is an important drug used in the control of multidrug-resistant Plasmodium falciparum malaria. However, the mechanism of action for this class of drugs, known as the artemisinins, and thus potential mechanisms for development of drug resistance remain poorly understood. Semimechanistic models of parasite dynamics have been proposed to explain the potential effects of drug on parasite sequestration in unmeasurable compartments (16,18). Selective effects of drug on early parasite ring stages were found to explain differences in parasite clearance observed between patients treated in Thailand and Cambodia using intrahost mathematical modeling of pharmacokinetic (PK)-pharmacodynamic (PD) relationships (36). Autoinduction of metabolism has been suggested for drugs in this class (15,17), representing a possible confounder to parasite-based mechanisms of resistance. The current models provide only limited explanations for artesunate resistance, creating an ongoing need for additional empirical data.We recently reported evidence of artesunate resistance in malaria parasites from patient...

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Section: Figmentioning

confidence: 54%

Section: Clinicalmentioning

confidence: 99%

Section: Clinicalmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Saunders

Khemawoot

Vanachayangkul

et al. 2012

Antimicrob Agents Chemother

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“…Adherence to the longer treatment course might hinder adherence, and interaction of the long half-life partner drugs will need to be assessed. It should also be noted that a total cumulative dose .20 mg/ kg of artesunate has been associated with bone marrow toxicity (Bethell et al 2010;Das et al 2013). Finally, a promising approach is the combination of artemisinin derivatives with two slowly eliminated partner drugs in a 3-d triple ACT.…”

Section: Future Perspectives: Toward the Elimination Of Artemisinin Amentioning

confidence: 99%

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Ménard¹,

Dondorp²

2017

Cold Spring Harb Perspect Med

389

339

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Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria

Haghiri,

Price,

Fitzpatrick

et al. 2023

Clin Pharma and Therapeutics

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The majority of deaths from malaria are in young African children. Parenteral artesunate is the first‐line treatment for severe falciparum malaria. Since 2015 the World Health Organization has recommended individual doses of 3 mg/kg for children weighing less than 20 kg. Recently, the US Food and Drug Administration (FDA) has challenged this recommendation, based on a simulated pediatric population, and argued for a lower dose in younger children (2.4 mg/kg). In this study, we performed population pharmacokinetic modeling of plasma concentration data from 80 children with severe falciparum malaria in the Democratic Republic of Congo who were given 2.4 mg/kg of artesunate intravenously. Bayesian hierarchical modeling and a two‐compartment parent drug‐metabolite pharmacokinetic model for artesunate were used to describe the population pharmacokinetics of artesunate and its main biologically active metabolite dihydroartemisinin. We then generated a virtual population representative of the target population in which the drug is used and simulated the total first‐dose exposures. Our study shows that the majority of younger children given the lower 2.4 mg/kg dose of intravenous artesunate do not reach the same drug exposures as older children above 20 kg. This finding supports withdrawal of the FDA's recent lower artesunate dose recommendation as parenteral artesunate is an extremely safe and well‐tolerated drug and there is potential for harm from underdosing in this rapidly lethal infection.

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Dose‐Dependent Risk of Neutropenia after 7‐Day Courses of Artesunate Monotherapy in Cambodian Patients with AcutePlasmodium falciparumMalaria

Cited by 50 publications

References 15 publications

Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia

Antimalarial Drug Resistance: A Threat to Malaria Elimination

Evidence Based Optimal Dosing of Intravenous Artesunate in Children with Severe Falciparum Malaria

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