Mechanism-Based Modelling of Artemisinin Combination Therapy in Murine Malaria
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Objectives: To develop a mechanistic model that describes the growth, antimalarial killing and recrudescence of parasite following dihydroartemisinin and piperaquine combination therapy to infected mice. Methods: Antimalarial drug concentration and parasite density data were obtained from Swiss mice inoculated with Plasmodium berghei. 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. A mechanism- based population model was developed using the Monte Carlo Expectation Maximization (MCPEM) algorithm in S-ADAPT. Para- site recrudescence was defined using a previously published structural model that incorporated each erythrocytic stage of the P. berghei lifecycle . Results: One- and two-compartment models described the disposition of dihydroartemisinin and piperaquine, respectively. The estimated mean 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 IC50 of 0.747 l g/L for dihydroartemisinin and 16.8 l g/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than that for piperaquine. Parameters from the monotherapy models adequately described the parasite density-time curve following combination therapy of dihydroartemisinin with piperaquine. Conclusions: This study has developed mechanistic models that describe the parasite-time curve after single, multiple or combination dosing of antimalarial drugs to mice. These structural models have potential application to design and refine dosage regimens for artemisinin-based combination therapy.
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Patel, K.; Batty, Kevin; Moore, Brioni; Gibbons, Peter; Kirkpatrick, C. (2014)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 ...
Moore, Brioni R. (2011)Murine malaria models have proved to be a valuable preclinical tool, particularly in the development of new concepts in the research of human malaria. Plasmodium berghei (P. berghei), is the most extensively studied and ...
Patel, K.; Batty, Kevin; Moore, Brioni; Gibbons, P.; Bulitta, J.; Kirkpatrick, C. (2013)Murine models are used to study erythrocytic stages of malaria infection, because parasite morphology and development are comparable to those in human malaria infections. Mechanism-based pharmacokinetic-pharmacodynamic ...