Clinical Pharmacokinetics

, Volume 37, Issue 1, pp 41–58 | Cite as

Population Pharmacokinetics

A Regulatory Perspective
  • He SunEmail author
  • Emmanuel O. Fadiran
  • Carolyn D. Jones
  • Lawrence Lesko
  • Shiew-Mei Huang
  • Karen Higgins
  • Chuanpu Hu
  • Stella Machado
  • Samuel Maldonado
  • Roger Williams
  • Mohammad Hossain
  • Ene I. Ette
Review Articles Concepts


The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants.

Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives.

The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of ‘good pharmacometric practice’.

Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data.

Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims.

The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as ‘Guidance for Industry: Population Pharmacokinetics’ (see the FDA home page for further information).


Adis International Limited Exploratory Data Analysis Population Pharmacokinetic Model Population Pharmacokinetic Study Standardise Prediction Error 
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Copyright information

© Adis International Limited 1999

Authors and Affiliations

  • He Sun
    • 1
    Email author
  • Emmanuel O. Fadiran
    • 1
  • Carolyn D. Jones
    • 2
  • Lawrence Lesko
    • 1
  • Shiew-Mei Huang
    • 1
  • Karen Higgins
    • 1
  • Chuanpu Hu
    • 1
  • Stella Machado
    • 1
  • Samuel Maldonado
    • 3
  • Roger Williams
    • 1
  • Mohammad Hossain
    • 4
  • Ene I. Ette
    • 5
  1. 1.Center for Drug Evaluation and ResearchFood and Drug AdministrationRockvilleUSA
  2. 2.Solvay PharmeceuticalMarietaUSA
  3. 3.Boehringer Ingelheim PharmeceuticalsRidgefieldUSA
  4. 4.Novartis PharmaceuticalsEast HanoverUSA
  5. 5.Vertex PharmaceuticalsCambridgeUSA

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