Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model
Objectives: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. Methods: Total parasite density–time data from Swiss mice inoculated with Plasmodium berghei were used...
| Main Authors: | , , , , |
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| Format: | Journal Article |
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Oxford University Press
2014
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| Online Access: | http://hdl.handle.net/20.500.11937/24949 |
| _version_ | 1848751570913591296 |
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| author | Patel, K. Batty, Kevin Moore, Brioni Gibbons, Peter Kirkpatrick, C. |
| author_facet | Patel, K. Batty, Kevin Moore, Brioni Gibbons, Peter Kirkpatrick, C. |
| author_sort | Patel, K. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Objectives: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. Methods: Total parasite density–time data from Swiss mice inoculated with Plasmodium berghei were used for the development of population models in S-ADAPT. The mice were administered a single intraperitoneal dose of 30 mg/kg dihydroartemisinin, 10 mg/kg piperaquine phosphate or a combination of both antimalarials at 64 h post-inoculation. In a separate study, mice received multiple dihydroartemisinin doses (5×10 mg/kg or 30 mg/kg dihydroartemisinin followed by two 10 mg/kg doses). Parasite recrudescence after treatment was defined using a model that incorporated each erythrocytic stage of the P. berghei life cycle. Results: The disposition of dihydroartemisinin and piperaquine was described by a one-compartment and two-compartment model, respectively. The estimated clearance was 1.95 L/h for dihydroartemisinin and 0.109 L/h for piperaquine. A turnover model described the parasite killing curve after single-agent dosing, with an estimated mean IC50 of 0.747 µg/L for dihydroartemisinin and 16.8 µg/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than for piperaquine. Parameters from the monotherapy models adequately described the parasite density–time curve following dihydroartemisinin/piperaquine combination therapy or multiple-dose regimens of dihydroartemisinin. Conclusions: This study has developed mechanistic models that describe the parasite–time curve after single, multiple or combination dosing of antimalarials to mice. These structural models have potential application for pre-clinical investigations to design and refine artemisinin-based combination therapy dosage regimens. |
| first_indexed | 2025-11-14T07:54:50Z |
| format | Journal Article |
| id | curtin-20.500.11937-24949 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T07:54:50Z |
| publishDate | 2014 |
| publisher | Oxford University Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-249492017-09-13T15:12:59Z Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model Patel, K. Batty, Kevin Moore, Brioni Gibbons, Peter Kirkpatrick, C. piperaquine mechanism-based modelling population pharmacodynamics dihydroartemisinin Plasmodium berghei Objectives: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. Methods: Total parasite density–time data from Swiss mice inoculated with Plasmodium berghei were used for the development of population models in S-ADAPT. The mice were administered a single intraperitoneal dose of 30 mg/kg dihydroartemisinin, 10 mg/kg piperaquine phosphate or a combination of both antimalarials at 64 h post-inoculation. In a separate study, mice received multiple dihydroartemisinin doses (5×10 mg/kg or 30 mg/kg dihydroartemisinin followed by two 10 mg/kg doses). Parasite recrudescence after treatment was defined using a model that incorporated each erythrocytic stage of the P. berghei life cycle. Results: The disposition of dihydroartemisinin and piperaquine was described by a one-compartment and two-compartment model, respectively. The estimated clearance was 1.95 L/h for dihydroartemisinin and 0.109 L/h for piperaquine. A turnover model described the parasite killing curve after single-agent dosing, with an estimated mean IC50 of 0.747 µg/L for dihydroartemisinin and 16.8 µg/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than for piperaquine. Parameters from the monotherapy models adequately described the parasite density–time curve following dihydroartemisinin/piperaquine combination therapy or multiple-dose regimens of dihydroartemisinin. Conclusions: This study has developed mechanistic models that describe the parasite–time curve after single, multiple or combination dosing of antimalarials to mice. These structural models have potential application for pre-clinical investigations to design and refine artemisinin-based combination therapy dosage regimens. 2014 Journal Article http://hdl.handle.net/20.500.11937/24949 10.1093/jac/dku120 Oxford University Press unknown |
| spellingShingle | piperaquine mechanism-based modelling population pharmacodynamics dihydroartemisinin Plasmodium berghei Patel, K. Batty, Kevin Moore, Brioni Gibbons, Peter Kirkpatrick, C. Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title | Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title_full | Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title_fullStr | Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title_full_unstemmed | Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title_short | Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| title_sort | predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model |
| topic | piperaquine mechanism-based modelling population pharmacodynamics dihydroartemisinin Plasmodium berghei |
| url | http://hdl.handle.net/20.500.11937/24949 |