Skip to main content

Prediction of Hepatic Metabolic Clearance Based on Interspecies Allometric Scaling Techniques and In Vitro-In Vivo Correlations

Clinical Pharmacokinetics volume 36, pages 211–231 (1999)Cite this article

Abstract

This article reviews the methods available for predicting hepatic metabolic clearance in humans, and discusses their application to the processes of drug discovery and development. The application of these techniques has increased markedly during the past few years because of the improved availability of human liver samples, which has increased the opportunities to use in vitro studies to predict human clearance. The techniques available involve both empirical and physiologically based approaches. Allometric scaling using in vitro data from animals and humans combines certain aspects of both approaches.

An evaluation of data retrieved from the literature indicates that, together with in vitro human data, allometric scaling based on a combination of in vitro and in vivo preclinical data can accurately predict clearance in humans. With this approach, 80% of the predictions were within a 2-fold factor of actual human clearance values, with an overall accuracy of 1.6-fold.

The uncertainties and inaccuracies in predicting human clearance are related to: (i) the specific method that is used to make the prediction; (ii) the experimental design and the model used to determine the in vitro clearance; (iii) protein binding within the in vitro test system; and (iv) various in vivo factors such as the involvement of extrahepatic metabolism and active transport processes, interindividual variability and nonlinearity in pharmacokinetics.

In contrast to purely empirical approaches, the physiological approach to predicting clearance gives an opportunity to integrate some of these complexities and, therefore, should provide more confidence in the prediction of clearance in humans.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Prentis RA, Lis Y, Walker SR. Pharmaceutical innovation by the seven UK-owned companies (1964–1985). Br J Clin Pharmacol 1988; 25: 387–96.

    PubMed  Article  CAS  Google Scholar 

  2. Boxenbaum H, Dilea C. First-time-in-human dose selection: allometric thoughts and perspectives. J Clin Pharmacol 1995; 35: 957–66.

    PubMed  CAS  Google Scholar 

  3. Bonati M, Latini R, Tognoni G, et al. Interspecies comparison of in vivo caffeine pharmacokinetics in human, monkey, rabbit, rat and mouse. Drug Metab Rev 1984; 15: 1355–83.

    PubMed  Article  CAS  Google Scholar 

  4. Brocks DR, Freed MI, Martin DE, et al. Interspecies pharmacokinetics of a novel hematoregulatory peptide (SK&F 107647) in rats, dogs, and oncologic patients. Pharm Res 1996; 13: 794–7.

    PubMed  Article  CAS  Google Scholar 

  5. Campbell DB. Can allometric interspecies scaling be used to predict human kinetics. Drug Inf J 1994; 28: 235–45.

    Article  Google Scholar 

  6. Gascon AR, Calvo B, Hernandez RM, et al. Interspecies scaling of cimetidine-theophylline pharmacokinetic interaction: interspecies scaling in pharmacokinetic interactions. Pharm Res 1994; 11(7): 945–50.

    PubMed  Article  CAS  Google Scholar 

  7. Ibrahim SS, Boudinot FD. Pharmacokinetics of 2′,3′-dideoxy-cytidine in rats: application to interspecies scale-up. J Pharm Pharmacol 1989; 41: 829–34.

    PubMed  Article  CAS  Google Scholar 

  8. Ings RM. Interspecies scaling and comparisons in drug development and toxicokinetics. Xenobiotica 1990; 20: 1201–31.

    PubMed  Article  CAS  Google Scholar 

  9. Khor SP, Amyx H, Davis ST, et al. Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data, pharmacokinetics and toxicodynamics of 5-fluorouracil in humans. Cancer Chemother Pharmacol 1997; 39: 233–8.

    PubMed  Article  CAS  Google Scholar 

  10. Lapka R, Rejholec V, Sechser T, et al. Interspecies pharmacokinetic scaling of metazosin, a novel alpha-adrenergic antagonist. Biopharm Drug Dispos 1989; 10: 581–9.

    PubMed  Article  CAS  Google Scholar 

  11. Lave T, Levettrafit B, Schmitthoffmann AH, et al. Interspecies scaling of interferon disposition and comparison of allometric scaling with concentration-time transformations. J Pharm Sci 1995; 84: 1285–90.

    PubMed  Article  CAS  Google Scholar 

  12. Lave T, Saner A, Coassolo P, et al. Animal pharmacokinetics and interspecies scaling from animals to man of lamifiban, a new platelet aggregation inhibitor. J Pharm Pharmacol 1996; 48: 573–7.

    PubMed  Article  CAS  Google Scholar 

  13. Lave T, Coassolo P, Ubeaud G, et al. Interspecies scaling of bosentan, a new endothelin receptor antagonist and integration of in vitro data into allometric scaling. Pharm Res 1996; 13: 97–101.

    PubMed  Article  CAS  Google Scholar 

  14. Lave T, Dupin S, Schmitt M, et al. Interspecies scaling of tolcapone, a new inhibitor of catechol-O-methyltransferase (COMT): use of in vitro data from hepatocytes to predict metabolic clearance in animals and humans. Xenobiotica 1996; 26: 839–51.

    PubMed  Article  CAS  Google Scholar 

  15. McNamara PJ. Interspecies scaling in pharmacokinetics. In: Welling PG, Tse FLS, Dighe SV, editors. Pharmaceutical bioequivalence. New York: Marcel Dekker, 1991: 267–300.

    Google Scholar 

  16. Mordenti J. Forecasting cephalosporin and monobactam antibiotic half-lives in humans from data collected in laboratory animals. Antimicrob Agents Chemother 1985; 27: 887–91.

    PubMed  Article  CAS  Google Scholar 

  17. Mordenti J. Pharmacokinetic scale-up: accurate prediction of human pharmacokinetic profiles from animal data. J Pharm Sci 1985; 74: 1097–9.

    PubMed  Article  CAS  Google Scholar 

  18. Mordenti J, Chen SA, Moore JA, et al. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm Res 1991; 8: 1351–9.

    PubMed  Article  CAS  Google Scholar 

  19. Mordenti J, Osaka G, Garcia K, et al. Pharmacokinetics and interspecies scaling of recombinant human factor VIII. Toxicol Appl Pharmacol 1996; 136: 75–8.

    PubMed  Article  CAS  Google Scholar 

  20. Obach RS, Baxter JG, Liston TE, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 1997; 283: 46–58.

    PubMed  CAS  Google Scholar 

  21. Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994; 47: 1469–79.

    PubMed  Article  CAS  Google Scholar 

  22. Rane A, Wilkinson GR, Shand DG. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J Pharmacol Exp Ther 1977; 200: 420–4.

    PubMed  CAS  Google Scholar 

  23. Rodriguez AD. Preclinical drug metabolism in the age of high throughput screening: an industrial perspective. Pharm Res 1997; 14: 1504–10.

    Article  Google Scholar 

  24. Lave T, Dupin S, Schmitt C, et al. The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans. Pharm Res 1997; 14: 152–5.

    PubMed  Article  CAS  Google Scholar 

  25. Reigner BG, Williams PEO, Patel JH, et al. An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development: experience within Hoffmann La Roche. Clin Pharmacokinet 1997; 33: 142–52.

    PubMed  Article  CAS  Google Scholar 

  26. Rahmani R, Richard B, Fabre G, et al. Extrapolation of preclinical pharmacokinetic data to therapeutic drug use. Xenobiotica 1988; 1: 71–88.

    Google Scholar 

  27. Carlile DJ, Zomorodi K, Houston JB. Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver: studies with induced livers involving diazepam. Drug Metab Dispos 1997; 25: 903–11.

    PubMed  CAS  Google Scholar 

  28. Ubeaud G, Schmitt C, Jaeck D, et al. Bosentan, a new endothelin receptor antagonist: prediction of the systemic plasma clearance in man from combined in vivo and in vitro data. Xenobiotica 1995; 25: 1381–90.

    PubMed  Article  CAS  Google Scholar 

  29. Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987; 39: 1–47.

    PubMed  CAS  Google Scholar 

  30. Iwatsubo T, Hirota N, Ooie T, et al. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol Ther 1997; 73: 147–71.

    PubMed  Article  CAS  Google Scholar 

  31. Hoener BA. Predicting the hepatic clearance of xenobiotics in humans from in vitro data. Biopharm Drug Dispos 1994; 15: 295–304.

    PubMed  Article  CAS  Google Scholar 

  32. Bäärnhielm C, Dählback H, Skanberg I. In vivo pharmacokinetics of felodipine predicted from in vitro studies in rat, dog and man. Acta Pharm Toxicol 1986; 59: 113–22.

    Article  Google Scholar 

  33. Juergens KD. Allometry as a tool for extrapolation of biological variables. Comp Biochem Physiol 1991; 100C: 287–90.

    Google Scholar 

  34. Adolph ER. Quantitative relations in the physiological contributions of mammals. Science 1949; 109: 579–85.

    PubMed  Article  CAS  Google Scholar 

  35. Mordenti J. Man versus beast: pharmacokinetic scaling in mammals. J Pharm Sci 1986; 75: 1028–40.

    PubMed  Article  CAS  Google Scholar 

  36. Holford NHG. A size Standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329–32.

    PubMed  Article  CAS  Google Scholar 

  37. Weiss M, Sziegoleit W, Forster W. Dependence of pharmacokinetic parameters on the body weight. Int J Clin Pharmacol 1977; 15: 572–5.

    CAS  Google Scholar 

  38. Boxenbaum B, D’souza RW. Interspecies pharmacokinetic scaling, biological design and neoteny. In: Testa B, editor. Advances in drug research. London: Academic Press Limited, 1990: 139–96.

    Google Scholar 

  39. Boxenbaum H. Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm. Drug Metab Rev 1984; 15: 1071–121.

    PubMed  Article  CAS  Google Scholar 

  40. Boxenbaum H, Fertig JB. Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species. Eur J Drug Metab Pharmacokinet 1984; 9: 177–83.

    PubMed  Article  CAS  Google Scholar 

  41. Yates FE, Kugler PN. Similarity principles and intrinsic geometries: contrasting approaches to interspecies scaling. J Pharm Sci 1986; 75: 1019–27.

    PubMed  Article  CAS  Google Scholar 

  42. Sacher GA. Relation of lifespan to brain weight and body weight in mammals. In: Wolstenholme G, O’Connor M, editors. The lifespan of animals. Boston: Little Brown & Co., 1959: 115–41.

    Google Scholar 

  43. Lave T, Schmitt-Hoffmann AH, Coassolo P, et al. Anew extrapolation method from animal to man: application to a metabolized compound, mofarotene. Life Sci 1995; 56: 473–8.

    Article  Google Scholar 

  44. Mahmood I, Balian JD. Interspecies scaling: predicting clearance of drugs in humans: three different approaches. Xenobiotica 1996; 26: 887–95.

    PubMed  Article  CAS  Google Scholar 

  45. Lave T, Dupin S, Schmitt C, et al. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man: application to 10 extensively metabolized drugs. J Pharm Sci 1997; 86: 584–90.

    PubMed  Article  CAS  Google Scholar 

  46. Boxenbaum M. Comparative pharmacokinetics of benzodiazepines in dog and man. J Pharmacokinet Biopharm 1982; 10: 411–26.

    PubMed  CAS  Google Scholar 

  47. Sawada Y, Hanano M, Sugiyama Y, et al. Prediction of the disposition of nine weakly acidic and six basic drugs in humans from pharmacokinetic parameters in rats. J Pharmacokinet Biopharm 1985; 13: 477–92.

    PubMed  CAS  Google Scholar 

  48. Bachmann K, Pardoe D, White D. Scaling basic toxicokinetic parameters from rat to man. Environ Health Perspect 1996; 104: 400–7.

    PubMed  Article  CAS  Google Scholar 

  49. Chiou WL, Choi YM. Unbound total (plasma) clearance approach in interspecies pharmacokinetics correlation: theophylline-cimetidine interaction. Pharm Res 1995; 12: 1238–9.

    PubMed  Article  CAS  Google Scholar 

  50. Cruze CA, Kelm GR, Meredith MP. Interspecies scaling of tebufelone pharmacokinetic data and application to preclinical toxicology. Pharmaceut Res 1995; 12: 895–901.

    Article  CAS  Google Scholar 

  51. Patel BA, Boudinot FD, Schinazi RF, et al. Comparative pharmacokinetics and interspecies scaling of 3′-azido-3′-deoxythymidine (AZT) in several mammalian species. J Pharmacobiodyn 1990; 13: 206–11.

    PubMed  Article  CAS  Google Scholar 

  52. Hutchaleelaha A, Chow HH, Mayersohn M. Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species. J Pharm Pharmacol 1997; 49: 178–83.

    PubMed  Article  CAS  Google Scholar 

  53. Elder CA, Modi MW. Interspecies scaling of a thienodiazepine platelet-activating factor receptor antagonist. Drug Metab Dispos 1995; 23: 776–8.

    PubMed  CAS  Google Scholar 

  54. Van Hoogdalem EJ, Soeishi Y, Matsushima H, et al. Disposition of the selective alphalA-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling. J Pharm Sci 1997; 86: 1156–61.

    PubMed  Article  Google Scholar 

  55. Izumi T, Enomoto S, Hosiyama K, et al. Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach. J Pharmacol Exp Ther 1996; 277: 1630–41.

    PubMed  CAS  Google Scholar 

  56. Mahmood I, Balian JD. Interspecies scaling: predicting pharmacokinetic parameters of antiepileptic drugs in humans from animals with special emphasis on clearance. J Pharm Sci 1996; 85: 411–4.

    PubMed  Article  CAS  Google Scholar 

  57. Owens SM, Hardwick WC, Blackall D. Phencyclidine pharmacokinetic scaling among species. J Pharmacol Exp Ther 1987; 242: 96–101.

    PubMed  CAS  Google Scholar 

  58. Paxton JW, Kim SN, Whitfield LR. Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, in mice, rats, rabbits, dogs, and humans. Cancer Res 1990; 50: 2692–7.

    PubMed  CAS  Google Scholar 

  59. Ritschel WA, Vachharajani NN, Johnson RD, et al. Interspecies scaling of the pharmacokinetic parameters of coumarin among six different mammalian species. Methods Find Exp Clin Pharmacol 1991; 13: 697–702.

    PubMed  CAS  Google Scholar 

  60. Sanwald-Ducray P, Dow J. Prediction of the pharmacokinetic parameters of reduced-dolasetron in man using in vitro-in vivo and interspecies allometric scaling. Xenobiotica 1997; 27: 189–201.

    PubMed  Article  CAS  Google Scholar 

  61. Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos 1995; 23: 1008–21.

    PubMed  CAS  Google Scholar 

  62. Laakso T, Artursson P, Sjoholm I. Biodegradable microspheres. IV: factors affecting the distribution and degradation of polyacryl starch microparticles. J Pharm Sci 1986; 75: 962–7.

    PubMed  Article  CAS  Google Scholar 

  63. Iwatsubo T, Hirota N, Ooie T, et al. Prediction of in vivo drug disposition from in vitro data based on physiological pharmacokinetics. Biopharm Drug Dispos 1996; 17: 273–310.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Cardiovascular Research, Pharmaceutical Division, R Hoffmann-La Roche Ltd, Basel, Switzerland

    Thierry Lavé & Philippe Coassolo

  2. Department of Clinical Pharmacology Science, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Bruno Reigner

  3. Pharmacokinetics and Drug Metabolism, Department of Cardiovascular Research, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070, Basel, Switzerland

    Thierry Lavé

Authors
  1. Thierry Lavé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philippe Coassolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno Reigner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thierry Lavé.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lavé, T., Coassolo, P. & Reigner, B. Prediction of Hepatic Metabolic Clearance Based on Interspecies Allometric Scaling Techniques and In Vitro-In Vivo Correlations. Clin Pharmacokinet 36, 211–231 (1999). https://doi.org/10.2165/00003088-199936030-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199936030-00003

Keywords

  • Adis International Limited
  • Bosentan
  • Intrinsic Clearance
  • Allometric Scaling
  • Hepatic Extraction Ratio