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Dose Linearity and Proportionality

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Drug Discovery and Evaluation: Methods in Clinical Pharmacology

Abstract

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.

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References and Further Reading

  • 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, Aachen

    Google Scholar 

  • EMEA CPMP (2010) Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr)

    Google Scholar 

  • EMEA CPMP (2014) Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 Corr1)

    Google Scholar 

  • 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/Heidelberg

    Google Scholar 

  • Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J (1995) Assessment of dose proportionality: report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Ther Innov Regul Sci 29(3):1039–1048

    Google Scholar 

  • 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. https://doi.org/10.1002/pst.326

    Article  PubMed  Google Scholar 

  • Ludden TM (1991) Nonlinear pharmacokinetics: clinical implications. Clin Pharmacokinet 20:429–446

    Article  CAS  PubMed  Google Scholar 

  • Sethuraman VS, Leonov S, Squassante L, Mitchell TR, Hale MD (2007) Sample size calculation for the Power Model for dose proportionality studies. Pharm Stat 6:35–41. https://doi.org/10.1002/pst.241

    Article  PubMed  Google Scholar 

  • Smith BP (2004) Assessment of dose proportionality. In: Bonate P (ed) Pharmacokinetics in drug development: vol 1, clinical study design and analysis. AAPS Press, Arlington

    Google Scholar 

  • 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 17:1278–1283

    Article  CAS  PubMed  Google Scholar 

  • US FDA (2001) Guidance for industry: statistical approaches to establishing bioequivalence. Office of Training and Communications, Division of Communications Management, Maryland

    Google Scholar 

  • US FDA (2014) Draft guideline for industry: bioavailability and bioequivalence studies submitted in NDAs or INDs – general considerations, Mar 2014

    Google Scholar 

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Correspondence to Tanja Eisenblaetter .

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Eisenblaetter, T., Teichert, L., Burnette, R., Hutson, P. (2018). Dose Linearity and Proportionality. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_5-1

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  • DOI: https://doi.org/10.1007/978-3-319-56637-5_5-1

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  • Print ISBN: 978-3-319-56637-5

  • Online ISBN: 978-3-319-56637-5

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