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- Lohy Das, Jesmin Permala
(författare)
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Modelling and Simulation to Improve Antimalarial Therapy
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Lohy Das, Jesmin, 1979-, et al.
(författare)
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Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia
- 2017
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 19:6, s. 1842-1854
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Lohy Das, Jesmin, 1979-, et al.
(författare)
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Population Pharmacokinetic and Pharmacodynamic Properties of Artesunate in Patients with Artemisinin Resistant Infections in Southern Myanmar
- 2018
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Ingår i: Malaria Journal. - : BioMed Central. - 1475-2875. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated. Methods: 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-effects modelling. Results: 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 dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 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. Conclusion: The pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.
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| 4. |
- Lohy Das, Jesmin, et al.
(författare)
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Population Pharmacokinetics of Artemether and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium Falciparum Malaria.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Lohy Das, Jesmin, 1979-, et al.
(författare)
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Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum Malaria
- 2018
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 62:10
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Tidskriftsartikel (refereegranskat)abstract
- The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n = 11) or third (n = 11) trimester with uncomplicated Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) for lumefantrine was 641 h . mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was 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 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.
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