A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum
Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization o...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Microbiology
2017
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| _version_ | 1797100808262647808 |
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| author | Cao, P Klonis, N Zaloumis, S Dogovski, C Xie, S Saralamba, S White, L Fowkes, F Tilley, L Simpson, J McCaw, J |
| author_facet | Cao, P Klonis, N Zaloumis, S Dogovski, C Xie, S Saralamba, S White, L Fowkes, F Tilley, L Simpson, J McCaw, J |
| author_sort | Cao, P |
| collection | OXFORD |
| description | Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization of dosing regimens and the development of strategies to prolong the life span of current first-line treatment options. Recent short-drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic (PK-PD) paradigm in which the killing rate depends only on drug concentration. Here, we introduce a dynamic stress model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to that of a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early-ring-stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is due primarily to a faster development of stress rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies. |
| first_indexed | 2024-03-07T05:42:53Z |
| format | Journal article |
| id | oxford-uuid:e630bdf8-707d-4dc3-96c4-0e958760b3ee |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:42:53Z |
| publishDate | 2017 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:e630bdf8-707d-4dc3-96c4-0e958760b3ee2022-03-27T10:29:27ZA Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparumJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e630bdf8-707d-4dc3-96c4-0e958760b3eeEnglishSymplectic Elements at OxfordAmerican Society for Microbiology2017Cao, PKlonis, NZaloumis, SDogovski, CXie, SSaralamba, SWhite, LFowkes, FTilley, LSimpson, JMcCaw, JArtemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization of dosing regimens and the development of strategies to prolong the life span of current first-line treatment options. Recent short-drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic (PK-PD) paradigm in which the killing rate depends only on drug concentration. Here, we introduce a dynamic stress model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to that of a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early-ring-stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is due primarily to a faster development of stress rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies. |
| spellingShingle | Cao, P Klonis, N Zaloumis, S Dogovski, C Xie, S Saralamba, S White, L Fowkes, F Tilley, L Simpson, J McCaw, J A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title | A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title_full | A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title_fullStr | A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title_full_unstemmed | A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title_short | A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum |
| title_sort | dynamic stress model explains the delayed drug effect in artemisinin treatment of plasmodium falciparum |
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