Advertisement

Prediction of Human Pharmacokinetics

  • Siamak Cyrus Khojasteh
  • Harvey Wong
  • Cornelis E. C. A. Hop
Chapter

Abstract

The prediction of human pharmacokinetics is an extremely difficult endeavor during the selection of drug candidates for further human clinical testing. Despite a variety of available in vitro and in vivo methodologies, successful predictions are still difficult when performing them prospectively. This chapter gives a general overview of in vitro and in vivo methodologies used to predict human pharmacokinetics.

Keywords

Hepatic Blood Flow PBPK Model Allometric Equation Microsomal Protein Intrinsic Clearance 
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.

List of Abbreviations

ADME

Absorption, distribution, metabolism, and excretion

BrW

Brain weight

CLhepatic

Hepatic clearance

CLint

Intrinsic clearance

CLu

Unbound clearance

F

Bioavailability

Fa

Fraction absorbed from the intestine

Fg

Fraction that escapes intestinal metabolism

Fh

Fraction that escapes hepatic metabolism

fu

Unbound fraction in blood/plasma

fumic

Unbound fraction in microsomes

fut

Unbound fraction in tissues

HPGL

Hepatocytes per gram of liver

IVIVE

In vitro–in vivo extrapolation

Km

Michaelis–Menten constant (i.e., substrate concentration when v is ½ of V max)

MLP

Maximum life span

MPPGL

Microsomal protein per gram of liver

MRT

Mean residence time

P450

Cytochrome P450

PBPK

Physiologically based pharmacokinetic model

PK

Pharmacokinetic

Pmicrosome

Amount of microsomal protein in the incubation

Q

Hepatic blood flow

Re/I

Ratio of binding proteins in extracellular fluid (except plasma) to binding proteins in plasma

t1/2(in vitro)

In vitro half-life

Vd

Volume of distribution

Vd,u

Unbound volume of distribution

Ve

Extracellular fluid volume

Vincubation

Incubation volume

Vmax

Maximum rate of the metabolic reaction

Vp

Plasma volume

Vr

“Remainder” of the fluid volume

References

  1. Akabane T, Tabata K, Kadono K et al (2010) A comparison of pharmacokinetics between humans and monkeys. Drug Metab Dispos 38:308–316PubMedCrossRefGoogle Scholar
  2. Baranczewski P, Stanczak A, Sundberg K et al (2006) Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep 58:453–472PubMedGoogle Scholar
  3. Barter ZE, Bayliss MK, Beaune PH et al (2007) Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. Curr Drug Metab 8:33–45PubMedCrossRefGoogle Scholar
  4. Beaumont K, Smith DA (2009) Does human pharmacokinetic prediction add significant value to compound selection in drug discovery research? Curr Opin Drug Disc Dev 12:61–71Google Scholar
  5. Chiou WL, Barve A (1998) Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res 15:1792–1795PubMedCrossRefGoogle Scholar
  6. Chiou WL, Jeong HY, Chung SM et al (2000) Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res 17:135–140PubMedCrossRefGoogle Scholar
  7. Chiou WL, Buehler PW (2002) Comparison of oral absorption and bioavailability of drugs between monkey and human. Pharm Res 19:868–874PubMedCrossRefGoogle Scholar
  8. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095PubMedCrossRefGoogle Scholar
  9. Hallifax D, Houston JB (2006) Binding of drugs to hepatic microsomes: comment and assessment of current prediction methodology with recommendation for improvement. Drug Metab Dispos. 34:724–726PubMedCrossRefGoogle Scholar
  10. Hu T-M, Hayton WL (2001) Allometric scaling of xenobiotic clearance: uncertainty versus universality. AAPS PharmSci 3:1–14CrossRefGoogle Scholar
  11. Kilford PJ, Gertz M, Houston JB, Galetin A (2008) Hepatocellular binding of drugs: correction for unbound fraction in hepatocyte incubations using microsomal binding or drug lipophilicity data. Drug Metab Dispos. 36:1194–1197PubMedCrossRefGoogle Scholar
  12. Mahmood I (2005) Interspecies pharmacokinetic scaling: principles and application of allometric scaling. Pine House Publishers, Rockville, MarylandGoogle Scholar
  13. Nagilla R, Ward KW (2004) A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to humans. J Pharm Sci 93:2522–2534PubMedCrossRefGoogle Scholar
  14. Obach RS, Baxter JG, Liston TE et al (1997) The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283:46–58PubMedGoogle Scholar
  15. Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350–1359PubMedGoogle Scholar
  16. Smith R, Jones RD, Ballard PG et al (2008) Determination of microsome and hepatocyte scaling factors for in vitro/in vivo extrapolation in the rat and dog. Xenobiotica 38:1386–1398PubMedCrossRefGoogle Scholar
  17. Tang H, Mayersohn M (2005) A novel method for prediction of human drug clearance by allometric scaling. Drug Metab Dispos 33:1297–1303PubMedCrossRefGoogle Scholar
  18. Tang H, Hussain A, Leal M et al (2007) Interspecies prediction of human drug clearance based on scaling data from one or two animal species. Drug Metab Dispos 35:1886–1893PubMedCrossRefGoogle Scholar
  19. Wajima T, Yano Y, Fukumura K et al (2004) Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles. J Pharm Sci 93:1890–1900PubMedCrossRefGoogle Scholar
  20. Ward KW, Smith BR (2004) A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. I Clearance Drug Metab Dispos 32:603–611CrossRefGoogle Scholar
  21. Zhang Y, Yao L, Lin J et al (2010) Lack of appreciable species differences in nonspecific microsomal binding. J Pharm Sci 99:3620–3627PubMedCrossRefGoogle Scholar

Additional Reading

  1. De Buck SS, Mackie CE (2007) physiologically based approaches towards the prediction of pharmacokinetics: in vitro–in vivo extrapolation. Expert Opin Drug Metab Toxicol 3:865–878PubMedCrossRefGoogle Scholar
  2. Houston JB, Carlile DJ (1997) Prediction of hepatic clearance from microsomes, hepatocytes and liver slices. Drug Metab Rev 29:891–922PubMedCrossRefGoogle Scholar
  3. McGinnity DF, Collington J, Austin RP et al (2007) Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. Curr Drug Metab 8:463–479PubMedCrossRefGoogle Scholar
  4. Obach RS (2001) The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Devel 4:36–44PubMedGoogle Scholar
  5. Pelkonen O, Turpeinen M (2007) In vitro–in vivo extrapolation of hepatic clearance: biological tools, scaling factors, model assumptions and correct concentrations. Xenobiotica 37:1066–1089PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Siamak Cyrus Khojasteh
    • 1
  • Harvey Wong
    • 1
  • Cornelis E. C. A. Hop
    • 1
  1. 1.Genentech, Inc.San FranciscoUSA

Personalised recommendations