Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model.
OBJECTIVE
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.
Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia kashyap.patel@monash.edu.
Kashyap
K
Patel
School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia West Coast Institute, Joondalup, WA, Australia.
Kevin T
KT
Batty
School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia.
Brioni R
BR
Moore
School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Department of Medical Technology & Physics, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Peter L
PL
Gibbons
Centre for Medicine Use and Safety, Monash University, Melbourne, VIC, Australia.
Carl M
CM
Kirkpatrick
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics / Q000627:therapeutic use; D037621:Artemisinins / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004338:Drug Combinations; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D059208:Parasite Load; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D011804:Quinolines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012008:Recurrence; D010879:Piperazines
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines
Plasmodium berghei; dihydroartemisinin; mechanism-based modelling; piperaquine; population pharmacodynamics