Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

Malaria Journal

Methodology

Katherine Smith¹  Susan A Charman²  Kris M Jamsen³  Sophie Zaloumis³  Julie A Simpson³  Ric N Price⁴  Joerg Moehrle⁵  Andrew Humberstone⁵  Javier Gamo-Benito⁶  James McCaw⁷ 

[1] Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, VIC 3052, Parkville, Australia;Department of Medical Biology, University of Melbourne, 3010, Parkville, VIC, Australia;Centre for Drug Candidate Optimisation, Monash University, Melbourne, Australia;Centre for Molecular, Environmental, Genetic & Analytic Epidemiology, Melbourne School of Population Health, University of Melbourne, Level 3, 207 Bouverie St, VIC 3053, Carlton, Australia;Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Australia;Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom;Medicines for Malaria Venture, Geneva, Switzerland;Tres Cantos Medicines Development Campus, Tres Cantos, Spain;Vaccine and Immunization Research Group, Murdoch Childrens Research Institute and Melbourne School of Population Health, University of Melbourne, Melbourne, Australia;

关键词: Plasmodium falciparum;    Pharmacokinetic-pharmacodynamic model;    Anti-malarial combination therapy;   

DOI  :  10.1186/1475-2875-11-303

 received in 2012-04-26, accepted in 2012-08-01,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundMechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed.MethodsThree anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach.ResultsThe simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous).ConclusionsThis simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.

【 授权许可】

CC BY   
© Zaloumis et al.; licensee BioMed Central Ltd. 2012