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Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Pharmacometrics Research Group)ORCID iD: 0000-0002-1242-3874
(Department of Medical Research, Yangon, Republic of the Union of Myanmar.)
(Department of Medical Research, Yangon, Republic of the Union of Myanmar.)
(Department of Medical Research, Yangon, Republic of the Union of Myanmar.)
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(English)In: The AAPS JournalArticle in journal (Refereed) Submitted
Abstract [en]

Artemisinins are the most effective antimalarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening our ability to control and eliminate malaria. This work was aimed at evaluating the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroarthemisinin, in patients with sensitive and resistant P. falciparummalaria infections in southern myanmar In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. Fifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg / kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effect models. The absorption of artesunate was best characterized by a transit compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroarthemisin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overalls, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test. In conclusion, the pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to distinguish between drug-sensitive and resistant infections in these patients. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. More than half of all patients treated in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights is potential clinical utility. 

Keyword [en]
malaria – resistance – parasite clearance – artemisinin – pharmacokinetics – pharmacodynamics – nonlinear mixed-effects modelling
National Category
Infectious Medicine
Research subject
Medical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-329952OAI: oai:DiVA.org:uu-329952DiVA: diva2:1143897
Funder
Wellcome trust
Available from: 2017-09-22 Created: 2017-09-22 Last updated: 2017-10-16
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. 75 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 239
Keyword
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: 2017-11-03

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