Making the most of clinical data:

Reviewing the role of pharmacokinetic-pharmacodynamic models of anti-malarial drugs

Julie Simpson, Sophie Zaloumis, Alysha M DeLivera, Ric Price, James McCaw

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation- estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates. � 2014 American Association of Pharmaceutical Scientists.
    Original languageEnglish
    Pages (from-to)962-974
    Number of pages13
    JournalAAPS Journal
    Volume16
    Issue number5
    DOIs
    Publication statusPublished - 2014

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    Antimalarials
    Parasites
    Pharmacokinetics
    Pharmaceutical Preparations
    Life Cycle Stages
    Drug Resistance
    Immunity
    Erythrocytes
    Growth
    Population
    Clinical Studies

    Cite this

    Simpson, Julie ; Zaloumis, Sophie ; DeLivera, Alysha M ; Price, Ric ; McCaw, James. / Making the most of clinical data: Reviewing the role of pharmacokinetic-pharmacodynamic models of anti-malarial drugs. In: AAPS Journal. 2014 ; Vol. 16, No. 5. pp. 962-974.
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    abstract = "Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation- estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates. � 2014 American Association of Pharmaceutical Scientists.",
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    Making the most of clinical data: Reviewing the role of pharmacokinetic-pharmacodynamic models of anti-malarial drugs. / Simpson, Julie; Zaloumis, Sophie; DeLivera, Alysha M; Price, Ric; McCaw, James.

    In: AAPS Journal, Vol. 16, No. 5, 2014, p. 962-974.

    Research output: Contribution to journalArticleResearchpeer-review

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    AU - Zaloumis, Sophie

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    AU - Price, Ric

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