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Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)ORCID iD: 0000-0002-1242-3874
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.ORCID iD: 0000-0001-5190-2395
Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.ORCID iD: 0000-0002-7951-0745
Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.ORCID iD: 0000-0002-0383-9624
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2017 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 19, no 6, p. 1842-1854Article in journal (Refereed) Published
Abstract [en]

Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

Place, publisher, year, edition, pages
2017. Vol. 19, no 6, p. 1842-1854
National Category
Pharmacology and Toxicology
Research subject
Population Biology
Identifiers
URN: urn:nbn:se:uu:diva-328533DOI: 10.1208/s12248-017-0141-1ISI: 000415057700027PubMedID: 28895080OAI: oai:DiVA.org:uu-328533DiVA, id: diva2:1136123
Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2018-02-23Bibliographically approved
In thesis
1. Modelling and Simulation to Improve Antimalarial Therapy
Open this publication in new window or tab >>Modelling and Simulation to Improve Antimalarial Therapy
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The introduction of artemisinin-based combination therapy (ACT) substantially reduced malaria-related mortality and morbidity during the past decade. Despite the widespread use of ACT, there is still a considerable knowledge gap with regards to safety, efficacy and pharmacokinetic properties of these drugs, particularly in vulnerable populations like children and pregnant women. In addition, there is growing evidence of widespread artemisinin-resistance across the Greater Mekong Subregion. Expedited delivery of novel antimalarial drugs with different mechanisms of action to the clinical setting is still far off; therefore, it is crucial to improve the use of existing antimalarial drugs for optimal outcome in order to prolong their therapeutic life span.

This thesis focuses on utilizing pharmacometric tools to support this effort for malaria prevention and treatment.

An extensive simulation framework was used to explore alternative malaria chemopreventive dosing regimens of a commonly used ACT, dihydroartemisinin-piperaquine. Different monthly and weekly dosing regimens were evaluated and this allowed an understanding of the interplay between adherence, loading dose and malaria incidence. A weekly dosing regimen substantially improved the prevention effect and was less impacted by poor adherence. This is also expected to reduce selection pressure for development of resistance to piperaquine.

Population pharmacokinetics-pharmacodynamic models were developed for artesunate and the active metabolite dihydroartemisinin, effect on parasite clearance, in patients with artemisinin-resistant and -sensitive malaria infections in Southeast Asia. The modeling identified an association between parasite density and drug bioavailability. It predicted the presence of high levels of artemisinin resistant infection among patients in Cambodia and its spread into Myanmar. A nomogram to identify patients with artemisinin resistant infections was developed. Furthermore, the model was used to demonstrate the need for extended treatment duration to treat patients with artemisinin resistant infections.

A population pharmacokinetic model developed from data on pregnant women in East Africa allowed further understanding of artemether-lumefantrine exposure in pregnant populations. It also suggested that the lumefantrine exposure in this population is not compromised.

In summary, the results presented in this thesis demonstrate the value of pharmacometric approaches for improving antimalarial drug treatment and prevention. This ultimately contributes to overcoming the prevailing challenges to malaria control.

Place, publisher, year, edition, pages
Upppsala: Acta Universitatis Upsaliensis, 2017. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 239
Keywords
pharmacometrics, pharmacokinetics, pharmacodynamics, malaria, artemisinin, weekly dosing, resistant, pregnant populations, intermittent preventive therapy, parasite clearance, day 3 positivity, nomogram
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy; Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-330113 (URN)978-91-513-0098-6 (ISBN)
Public defence
2017-11-24, Room B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2017-11-03 Created: 2017-09-26 Last updated: 2018-01-13

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Lohy Das, JesminKarlsson, Mats OBergstrand, Martin

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