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Modelling and Simulation to Improve Antimalarial Therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)ORCID iD: 0000-0002-1242-3874
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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 [en]
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: urn:nbn:se:uu:diva-330113ISBN: 978-91-513-0098-6 (print)OAI: oai:DiVA.org:uu-330113DiVA: diva2:1144282
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
List of papers
1. Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine
Open this publication in new window or tab >>Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 5, e02491-16Article in journal (Refereed) Published
Abstract [en]

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted similar to 4% malaria incidence per year compared to similar to 8% for dosing regimen of two tablets weekly and similar to 10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-328099 (URN)10.1128/aac.02491-16 (DOI)000403532100060 ()
Funder
Wellcome trust
Available from: 2017-08-17 Created: 2017-08-17 Last updated: 2017-10-19Bibliographically approved
2. Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
Open this publication in new window or tab >>Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
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2017 (English)In: American Association of Pharmaceutical Scientists (AAPS)Article in journal (Refereed) Accepted
National Category
Medical and Health Sciences
Research subject
Population Biology
Identifiers
urn:nbn:se:uu:diva-328533 (URN)
Note

Orally administered artemisinin-based combination therapy is the first line treatment against uncomplicated P. falciparum malaria worldwide. Men, den stigende forekomsten af ​​artemisinin resistens er truende forsøg på at behandle og eliminere malaria i Southeast Asia. Deze studie was gericht op het karakteriseren van de blootstelling-respons-relatie van artesunate bij patiënten met artemisinine-gevoelige en resistente malaria-infecties. Patients were recruited in Pailin, Cambodia (n = 39) and Wang Pa, Thailand (n = 40), and either received 2 mg / kg / day of artesunate monotherapy for 7 consecutive days or 4 mg / kg / day of artesunate monotherapy. 3 consecutive days followed by mefloquine 15 mg / kg and 10 mg / kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroarthemisinin, And microscopy-based parasitic densities were measured and evaluated using nonlinear mixed-effect models. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had significantly slower parasite clearance compared to Thailand patients. The pharmacokinetic properties of artesunate and dihydroartemisin were well described by transit compartment absorption followed by one-compartment disposition models. Parasite density was asignificant covariate and higher parasitic densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixing 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 rate.

Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2017-10-16
3. Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar
Open this publication in new window or tab >>Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern 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
malaria – resistance – parasite clearance – artemisinin – pharmacokinetics – pharmacodynamics – nonlinear mixed-effects modelling
National Category
Infectious Medicine
Research subject
Medical Pharmacology
Identifiers
urn:nbn:se:uu:diva-329952 (URN)
Funder
Wellcome trust
Available from: 2017-09-22 Created: 2017-09-22 Last updated: 2017-10-16
4. Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated  Plasmodium Falciparum  Malaria.
Open this publication in new window or tab >>Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated  Plasmodium Falciparum  Malaria.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Artemisinin-based combination therapy (artemether-lumefantrine) is commonly used in pregnant malaria patients. Men, effekten af ​​svangerskabsrelaterede ændringer på eksponering er uklar og svangerskabet har været forbundet med reduceret effektivitet i tidligere studier. Denne undersøgelse har som mål at karakterisere befolkningen af ​​artemether farmakokinetik, dets aktive metabolit dihydroarthemisinin og lumefantrin hos toogtyve rwandiske gravide kvinder i anden og tredje trimester med ukompliceret Plasmodium falciparum malaria.

These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combi­nation of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Venous plasma concentrations were quantified for all three analytes using liquid chro­matography coupled to tandem mass spectroscopy and analysed using nonlinear mixed-effects modelling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 hours, followed by a bi-phasic dis­position model. The median AUC0-∞was 641 μmg / L. Model-based simulations indicated that 11.7% of patients did not reach the target day 7 plasma concentration (280 ng / ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether were time dependent and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 hours and the oral clearance of ARM at opportunity 1, increased 1.43 fold, compared at occasion 6. While lumefantrine pharmacokinetic target attainment appeared reassuring in Rwandan pregnant women, especially compared to target achievement in Southeast Asia , larger cohorts will be required to confirm this finding. 

National Category
Infectious Medicine
Research subject
Biopharmaceutics; Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-330111 (URN)
Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-16

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