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The Bayesian approach to Population pharmacokinetic/pharmacodynamic modeling

  • Jon Wakefield
  • Leon Aarons
  • Amy Racine-Poon
Part of the Lecture Notes in Statistics book series (LNS, volume 140)

Abstract

It is one of the principal aims of drug development to discover, for a particular agent, the relationship between dose administered, drug concentrations in the body and efficacy/toxicity. Understanding this relationship leads to the determination of doses which are both effective and safe. Population pharmacokinetic/pharmacodynamic models provide an important aid to this understanding.

Pharmacokinetics considers the absorption, distribution and elimination over time of a drug and its metabolites. Pharmacokinetic data consist of drug concentrations along with (typically) known sampling times and known dosage regimens. A dosage regimen is defined by a route of administration and the sizes and timings of the doses. Pharmacodynamics considers the action of a drug on the body. Pharmacodynamic data consist of a response measure, for example blood pressure, a pain score or a clotting time, and a known dosage regimen. Population data arise when these quantities are measured on a group of individuals, along with subject-specific characteristics (covariates) such as age, sex or the level of a biological marker. When identical doses are administered to a group of individuals large between-individual variability in responses is frequently observed. The mechanisms which cause this variability are complex and include between-individual differences in both pharmacokinetic and pharmacodynamic parameters. The general aim of population studies then is to isolate and quantify the within-and between-individual sources of variability. The explanation of between-individual sources of variability in terms of known covariates is important as it has implications for the determination of dosage regimens for particular covariate-defined subpopulations.

In this chapter we describe the drug development process from a population pharmacokinetic/pharmacodynamic perspective. In particular we describe how the nature of the statistical analysis and the models that are used are modified as the type of data and the aims of the study change through the various phases of development. The Bayesian approach to population modeling is particularly appealing from a biological perspective as it allows informative prior distributions to be incorporated. These priors may arise from previous studies and/or from medical/biological considera-tions. From an estimation standpoint a Bayesian approach is preferable because of the difficulties which a classical approach encounters due to the large numbers of parameters, the nonlinearity of the subject-specific models which are typically used and the large numbers of variance parameters.

We illustrate the population approach to drug development by describing a number of studies which were carried out by Ciba for a particular anti-clotting agent. We also present a detailed analysis for one of the studies.

Keywords

Drug Development Bayesian Approach Subcutaneous Dose Compartmental System Nonlinear Mixed Effect Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Jon Wakefield
  • Leon Aarons
  • Amy Racine-Poon

There are no affiliations available

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