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

Zaloumis, Sophie, Humberstone, Andrew, Charman, Susan A., Price, Ric N., Moehrle, Joerg, Gamo-Benito, Javier, McCaw, James, Jamsen, Kris M., Smith, Katherine and Simpson, Julie A. (2012). Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development. Malaria Journal,11(303):1-14.

Document type: Journal Article
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NHMRC Grant No. 1035261
Title Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development
Author Zaloumis, Sophie
Humberstone, Andrew
Charman, Susan A.
Price, Ric N.
Moehrle, Joerg
Gamo-Benito, Javier
McCaw, James
Jamsen, Kris M.
Smith, Katherine
Simpson, Julie A.
Journal Name Malaria Journal
Publication Date 2012
Volume Number 11
Issue Number 303
ISSN 1475-2875   (check CDU catalogue  open catalogue search in new window)
Scopus ID 2-s2.0-84865458780
Start Page 1
End Page 14
Total Pages 14
Place of Publication United Kingdom
Publisher BioMed Central Ltd.
HERDC Category C1 - Journal Article (DIISR)
Abstract Background
Mechanistic 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.

Methods
Three 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.

Results
The 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).

Conclusions

This 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.
Keywords Plasmodium falciparum
Pharmacokinetic-pharmacodynamic model
Antimalarial combination therapy
DOI http://dx.doi.org/10.1186/1475-2875-11-303   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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