Dose Linearity and Proportionality

  • Tanja EisenblaetterEmail author
  • Lenore Teichert
  • Ronald Burnette
  • Paul Hutson
Living reference work entry


A desirable characteristic of a drug is linear pharmacokinetic properties to facilitate dose and dose regimen adjustment in patients. “Linear pharmacokinetics” implies that any concentration–time profiles normalized for dose and time are superimposable (Ludden 1991). Thus, one of the necessary conditions for linear pharmacokinetics is dose proportionality, and its assessment is a fundamental pharmacokinetic analysis conducted during the clinical development of a new drug candidate.

References and Further Reading

  1. Cawello W, Brett M, Weimann H-J, Zimmerman H, Pabst G, Sierakowski B, Gieschke R, Baumann A (1999) Parameters for compartment-free pharmacokinetics: standardisation of study design, data analysis, and reporting. Shaker Verlag, AachenGoogle Scholar
  2. EMEA CPMP (2010) Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr)Google Scholar
  3. EMEA CPMP (2014) Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1)Google Scholar
  4. Frick A, Marshallsay C, Steinstraesser WR (2006) Clinical studies – typical designs. In: Vogel HG, Maas J, Mayer D, Hock F (eds) Drug discovery and evaluation: safety and pharmacokinetic assays. Springer, Berlin/HeidelbergGoogle Scholar
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  6. Hummel J, McKendrick S, Brindley C, French R (2009) Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat 8:38–49. CrossRefPubMedGoogle Scholar
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  9. Smith BP (2004) Assessment of dose proportionality. In: Bonate P (ed) Pharmacokinetics in drug development: vol 1, clinical study design and analysis. AAPS Press, ArlingtonGoogle Scholar
  10. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST (2000) Confidence interval criteria for assessment of dose proportionality. Pharm Res 17:1278–1283CrossRefPubMedGoogle Scholar
  11. US FDA (2001) Guidance for industry: statistical approaches to establishing bioequivalence. Office of Training and Communications, Division of Communications Management, MarylandGoogle Scholar
  12. US FDA (2014) Draft guideline for industry: bioavailability and bioequivalence studies submitted in NDAs or INDs – general considerations, Mar 2014Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Tanja Eisenblaetter
    • 1
    Email author
  • Lenore Teichert
    • 2
  • Ronald Burnette
    • 3
  • Paul Hutson
    • 3
  1. 1.MünchenGermany
  2. 2.Biostatistics, Sanofi-Aventis Deutschland GmbHFrankfurt am MainGermany
  3. 3.University of Wisconsin School of PharmacyMadisonUSA

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