Investigating the Efficacy of Triple Artemisinin-Based Combination Therapies for Treating Plasmodium falciparum Malaria Patients Using Mathematical Modeling

Dini, Saber; Zaloumis, Sophie; Cao, Pengxing; Price, Ric N.; Fowkes, Freya J. I.; Pluijm, Rob W van der; McCaw, James M.; Simpson, Julie A.

doi:10.1128/aac.01068-18

Cited by 46 publications

(40 citation statements)

References 49 publications

(69 reference statements)

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“…Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) is an emerging threat to the improvements made for past decade in the strive to control and eliminate malaria [1]. Alternative strategies to protect the therapeutic lifespan of artemisinin-based combinations are being explored, such as extending the ACT treatment duration, optimizing drug dosing, new combinations and use of triple ACT as development of new anti-malarial drugs with comparable efficacy is underway [2][3][4][5][6]. Among studies that explored the efficacy and safety of extended ACT, such as artemether-lumefantrine, i.e.…”

Section: Introductionmentioning

confidence: 99%

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

Mhamilawa

Wikström

Mmbando

et al. 2020

Malar J

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Background: Extended artemisinin-based combination therapy (ACT) for treatment of uncomplicated Plasmodium falciparum malaria with already existing drug regimens, such as artemether-lumefantrine, might be effective in tackling the emerging ACT resistance. However, given the history of cardiotoxicity among anti-malarial drugs structurally similar to lumefantrine, the potential effect of extended artemether-lumefantrine treatment on the electrocardiographic (ECG) QTc interval is of high concern. Methods: Male and non-pregnant females aged 1-65 years, diagnosed with uncomplicated P. falciparum malaria in Bagamoyo district, Tanzania, were randomized into two arms. The intervention arm received an extended, i.e. 6-day, course of artemether-lumefantrine and an additional single low-dose primaquine (0.25 mg/kg) administered together with the last artemether-lumefantrine dose. The control arm received the standard weight-based 3-day course. ECGs were performed at day 0 and 4-5 h after the last dose at day 5. QT intervals were read manually using the tangent method and automatically. Bazett's (QTcB) and Fridericia's (QTcF) formulae were used for correction for heart rate. Descriptive statistics were used to calculate baseline characteristics and the number of supra-thresholds QTc intervals (QTc prolongation > 500, change in QTc interval (ΔQTc) > 60 ms). The mean change in QTc interval in and between the two arms was compared using the paired t-test and independent samples t-test, respectively. Results: A total of 195 patients were enrolled, 103 and 92 in the intervention and control arm, respectively. No patient experienced QTc intervals > 500 ms on day 5 by both formulae. Patients with ΔQTc > 60 ms, for QTcF were 6/103 (5.8%) vs 2/92 (2.2%) and for QTcB 2/103 (1.9%) vs 1/92 (1.1%) in the intervention and control arms, respectively. The mean difference in ΔQTc interval was statistically significant between the two arms with both correction formulae, 11.4 ms (95% CI 2.7-20.0, p = 0.010) and 13.4 ms (95% CI 5.3-21.5, p = 0.001), for QTcB and QTcF, respectively. Conclusion: The extended 6-day course of artemether-lumefantrine did not reveal clinically relevant QTc prolonging effects. However, significant QTcF prolongation and presence of patients with supra-threshold QTc values observed

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Section: Introductionmentioning

confidence: 99%

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

Mhamilawa

Wikström

Mmbando

et al. 2020

Malar J

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“…Within‐host mathematical modeling accommodating biological details (drug‐drug interaction, stage specificity of parasite killing, between‐patient variability, and between‐isolate variability) suggests the optimal mefloquine dose of three 6.7 mg/kg doses. The parasitological efficacy is higher than the currently recommended dose (8.3 mg/kg doses) 116 . It is finally proposed three 8.3 mg/kg mefloquine doses in dihydroartemisinin‐piperaquine to improve the clinical efficacy of dihydroartemisinin‐piperaquine in resistant areas.…”

Section: Artemisinins and Actsmentioning

confidence: 72%

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

Karbwang

Na‐Bangchang

2020

The Journal of Clinical Pharma

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Malaria remains one of the major global public health problems due to the emergence and spread of multidrug‐resistant Plasmodium falciparum. In recent years, clinical pharmacology has significantly contributed to the optimal dosing regimens of antimalarial drugs. The application of pharmacometric modeling and simulation has assisted in the accurate characterization of pharmacokinetic‐pharmacodynamic relationships and the optimization of the dosage regimens of existing antimalarial drugs, including new antimalarial candidates for multidrug‐resistant P falciparum in different populations.

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“…By aggregating all ACT within a single analysis, direct assessment of known AmE limitations related to the efficacy of the partner drug (e.g., Artesunate-sulfadoxine-pyrimethamine) were not possible. These limitations include administration aspects, such as duration of treatment and the number of tablets in the dose regimens of the partner drugs [99,100]. This could be a possible explanation for the lower drug effectiveness observed in Djibouti, Ecuador, India, Pakistan, and Sudan.…”

Section: Discussionmentioning

confidence: 99%

“…However, even the most recently developed ACT, DHAP, faces a threat of resistance in some parts of the Greater Mekong Region [101]. Current efforts to sustain effective treatment of falciparum malaria in such areas include introduction of the triple artemisinin-based combination therapy (TACT) [99]. Lack of data on drug resistance prevented this important parameter from being included within the AmE models.…”

Section: Discussionmentioning

confidence: 99%

Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991–2019

Rathmes

Rumisha

Lucas

et al. 2020

Malar J

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Background Anti-malarial drugs play a critical role in reducing malaria morbidity and mortality, but their role is mediated by their effectiveness. Effectiveness is defined as the probability that an anti-malarial drug will successfully treat an individual infected with malaria parasites under routine health care delivery system. Anti-malarial drug effectiveness (AmE) is influenced by drug resistance, drug quality, health system quality, and patient adherence to drug use; its influence on malaria burden varies through space and time. Methods This study uses data from 232 efficacy trials comprised of 86,776 infected individuals to estimate the artemisinin-based and non-artemisinin-based AmE for treating falciparum malaria between 1991 and 2019. Bayesian spatiotemporal models were fitted and used to predict effectiveness at the pixel-level (5 km × 5 km). The median and interquartile ranges (IQR) of AmE are presented for all malaria-endemic countries. Results The global effectiveness of artemisinin-based drugs was 67.4% (IQR: 33.3–75.8), 70.1% (43.6–76.0) and 71.8% (46.9–76.4) for the 1991–2000, 2006–2010, and 2016–2019 periods, respectively. Countries in central Africa, a few in South America, and in the Asian region faced the challenge of lower effectiveness of artemisinin-based anti-malarials. However, improvements were seen after 2016, leaving only a few hotspots in Southeast Asia where resistance to artemisinin and partner drugs is currently problematic and in the central Africa where socio-demographic challenges limit effectiveness. The use of artemisinin-based combination therapy (ACT) with a competent partner drug and having multiple ACT as first-line treatment choice sustained high levels of effectiveness. High levels of access to healthcare, human resource capacity, education, and proximity to cities were associated with increased effectiveness. Effectiveness of non-artemisinin-based drugs was much lower than that of artemisinin-based with no improvement over time: 52.3% (17.9–74.9) for 1991–2000 and 55.5% (27.1–73.4) for 2011–2015. Overall, AmE for artemisinin-based and non-artemisinin-based drugs were, respectively, 29.6 and 36% below clinical efficacy as measured in anti-malarial drug trials. Conclusions This study provides evidence that health system performance, drug quality and patient adherence influence the effectiveness of anti-malarials used in treating uncomplicated falciparum malaria. These results provide guidance to countries’ treatment practises and are critical inputs for malaria prevalence and incidence models used to estimate national level malaria burden.

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Investigating the Efficacy of Triple Artemisinin-Based Combination Therapies for Treating Plasmodium falciparum Malaria Patients Using Mathematical Modeling

Cited by 46 publications

References 49 publications

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

Global estimation of anti-malarial drug effectiveness for the treatment of uncomplicated Plasmodium falciparum malaria 1991–2019

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