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Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, Vss and t1/2 be predicted fromin-vivo rat data?

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In a drug discovery environment, reasonable go/no-go humanin-vivo pharmacokinetic (PK) decisions must be made in a timely manner with a minimum amount of animalin-vivo orin-vitro data. We have investigated the accuracy of thein-vivo correlation between rat and human for the prediction of the total systemic clearance (CL), the volume of distribution at steady state (Vss), and the half-life (t1/2) using simple allometric scaling techniques. We have shown, using a large diverse set of drugs, that a fixed exponent allometric scaling approach can be used to predict humanin-vivo PK parameters CL, Vss and t1/2 solely from ratin-vivo PK data with acceptable accuracy for making go/no-go decisions in drug discovery. Humanin-vivo PK predictions can be obtained using the simple allometric scaling relationships CLHuman ≈ 40 CLRat (L/hr), Vss Human ≈ 200 Vss Rat (L), and t1/2 Human ≈ 4 t1/2 Rat (hr). The average fold error for human CL predictions for N=176 drugs was 2.25 with 79% of the drugs having a fold error less than 3. The average fold error for human Vss predictions for N=144 drugs was 1.85 with 84% of the drugs having a fold error less than 3. The average fold error for human t1/2 predictions for N=145 drugs was 2.05 with 76% of the drugs having a fold error less than 3. Using these simple allometric relationships, the sorting of drug candidates into a low/medium/high/very high human classification scheme was also possible from rat data. Since these simple allometric relationships between rat and human CL, Vss, and t1/2 are reasonably accurate, easy to remember and simple to calculate, these equations should be useful for making early go/no-goin-vivo human PK decisions for drug discovery candidates.

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References

  1. Caldwell, J. (1996). The importance of drug metabolism studies for efficient drug discovery and development. Yakubutsu Dotai 11 (1), 119–26.

    CAS  Google Scholar 

  2. Smith, D. A.; Jones, B. C.; Walker, D. K. (1996). Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Med Res Rev 16(3), 243–266.

    Article  CAS  PubMed  Google Scholar 

  3. Rodrigues, A. D. (1997). Preclinical drug metabolism in the age of high-throughput screening: an industrial perspective. Pharm Res 14(11), 1504–1510.

    Article  CAS  PubMed  Google Scholar 

  4. Tarit, M. H.; Berman, J. (1998). High-throughput approaches for evaluating absorption distribution, metabolism and excretion properties of lead compounds. Curr Opin in Chem Bio 2, 411–416.

    Article  Google Scholar 

  5. Sinko, P. J. (1999). Drug selection in early drug development: screening for acceptable pharmacokinetic properties using combined in vitro and computational approaches. Curr Opin in Drug Discov Develop 2(1), 42–48.

    CAS  Google Scholar 

  6. Caldwell, G. W. (2000). Compound optimization in early- and late-phase drug discovery: acceptable pharmacokinetic properties utilizing combined physicochemical, in vitro and in vivo screens. [Published erratum appears in Curr Opin in Drug Discov Develop 2000, 3(2), 250], Curr Opin in Drug Discov Devel 3(1), 30–41.

    CAS  Google Scholar 

  7. Caldwell, G. W.; Ritchie, D. M.; Masucci, J. A.; Hageman, W. (2001). The new pre-preclinical paradigm: compound optimization in early and late phase drug discovery. Curr Top in Med Chem 1(5), 353–366.

    Article  CAS  Google Scholar 

  8. Robert, S. A. (2003). Drug metabolism and pharmacokinetics in drug discovery. Curr Opin in Drug Discov Develop 6(1), 66–80.

    Google Scholar 

  9. Caldwell, G. W.; Yan, Z.; Masucci, J. A.; Hageman, W.; Ritchie, D. M. (2003). Applied Pharmacokinetics in Drug Development. An Overview of Drug Discovery. Pharm Dev Regul 1(2), 117–132.

    Google Scholar 

  10. Macdonald, S. J. F.; Smith, P. W. (2001). Lead optimization in 12 months? True confessions of a chemistry team. Drug Discov Today 6(18), 947–953.

    Article  PubMed  Google Scholar 

  11. Bachmann, K. A.; Ghoshh, R. (2001). The use ofin-vitro methods to predictin-vivo pharmacokinetics and drug interactions. Curr Drug Metab 2, 299–314.

    Article  CAS  PubMed  Google Scholar 

  12. Smith, D.; Schmid, E.; Jones, B. (2002). Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery? Clin Pharmacokinet 41(13), 1005–1019.

    Article  CAS  PubMed  Google Scholar 

  13. Obach, R. S; Baxter, J G.; Liston, T E.; Silber, B. M; Jones, B C; Macintyre, F; Ranee, D J.; Wastall, P. (1997). The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 283(1), 46–58.

    CAS  PubMed  Google Scholar 

  14. Obach, R. S. (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(11), 1350–1359.

    CAS  PubMed  Google Scholar 

  15. Obach, R. S (2001). The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin in Drug Discov Develop 4(1), 36–44.

    CAS  Google Scholar 

  16. McGinnity, D. F.; Riley, R. J. (2001). Predicting drug pharmacokinetics in humans from in vitro metabolism studies. Biochemical Society Transactions 29(2), 135–139.

    Article  CAS  PubMed  Google Scholar 

  17. Lave, Th.; Dupin, S.; Schmitt, C, Vallès, B.; Ubeaud, G.; Chou, R. C.; Jaeck, D.; Coassolo, Ph. (1997). The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans. Pharm Res 14(2), 152–155.

    Article  CAS  PubMed  Google Scholar 

  18. Caldwell, G. W.; Masucci, J. A.; Chacon, E. (1999). High throughput liquid chromatography-mass spectrometry assessment of the metabolic activity ofcommercially available hepatocytes from 96-well plates. Comb Chem High Throughput Screening 2(1), 39–51.

    CAS  Google Scholar 

  19. Lau, Y. Y.; Sapidou, E.; Cui, X.; White, R. E.; Cheng, K.-C. (2002). Development of a novel in vitro model to predicthepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Metab Dispos 30(12), 1446–1454.

    Article  CAS  PubMed  Google Scholar 

  20. Iwatsubo, T.; Hirota, N.; Ooie, T.; Suzuki, H.; Shimada, N.; Chiba, K.; Ishizaki, T.; Green, C. E.; Tyson, CA.; Sugiyama, Y. (1997). Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol. Ther. 73(2), 5147–171.

    CAS  Google Scholar 

  21. Lombardo, F.; Obach, R. S.; Shalaeva, M. Y.; Gao, F. (2002). Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem 45, 2867–2876.

    Article  CAS  PubMed  Google Scholar 

  22. Hosseini-Yeganeh, M.; McLachlan, A. J. (2002). Physiologically based pharmacokinetic model for terbinafine in rats and humans. Antimicro Agents Chemother 46(7), 2219–2228.

    Article  CAS  Google Scholar 

  23. Mahmood, I. (1999). Allometric Issues in Drug Development. J Pharm Sei 88(11), 1101–1106.

    Article  CAS  Google Scholar 

  24. Feng, M. R.; Lou, X.; Brown, R. R.; Hutchaleelaha, A. (2000). Allometric Pharmacokinetics Scaling. Towards the Prediction of Human Oral pharmacokinetics. Pharm Res, 17(4), 410–418.

    Article  CAS  PubMed  Google Scholar 

  25. Boxenbaum, H. (1982). Interspecies scaling, allometry, physiological time and the ground plan of pharmacokinetics. J. Pharmacokinet Biopharm 10, 201–227.

    Article  CAS  PubMed  Google Scholar 

  26. Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.; Broske, L.; Nomeir, A. A.; Lin, C.-C; Cayen, M. N.; Barr, W. H. (1999). Novelin-vivo procedure for rapid pharmacokinetic screeningof discovery compounds in rats. Drug Discov Today 4(5), 232–237.

    Article  CAS  PubMed  Google Scholar 

  27. Hu, T.-M.; Hayton, W. L. (2001). Allometric scaling of xenobiotic clearance: uncertainty versus universality. PharmSci [online computer file; www.pharmsci.org/scientificjournals/pharmsci/journal/01_29.html] 3(4), Article 29.

  28. Chiou, W.L.; Robbie, G.; Chung, S. M.; Wu, T-C; Ma, C. (1998). Correlation of plasma clearance of 54 extensively metabolized drugs between humans and rats: mean allometric coefficient of 0.66. Pharm Res 15(9), 1474–1479.

    Article  CAS  PubMed  Google Scholar 

  29. Lave, T.; Coassolo, P.; Reigner, B. (1999). Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations. Clin Pharmacokinet 36(3), 211–231.

    Article  CAS  PubMed  Google Scholar 

  30. Wajima, T.; Fukumura, K.; Yano, Y.; Oguma, T. (2002). Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis. J Pharm Sei 91( 12), 2489–2499.

    Article  CAS  Google Scholar 

  31. Mahmood, L. (1999). Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study. J Pharm Pharmacol 51(8), 905–910.

    Article  CAS  PubMed  Google Scholar 

  32. Mahmood, I.; Balian, J. D. (1996). Interspecies scaling: A comparative study for the prediction of clearance and volume using two or more than two species. Life Sei 593, 579–585.

    Article  Google Scholar 

  33. Szakacs, T; Veres, Z; Vereczkey, L. (2001). In vitro-in vivo correlation of the pharmacokinetics of vinpocetine. Polish J Pharmacol 53(6), 623–628.

    CAS  Google Scholar 

  34. Spasov, A. A.; Stepanov, A.V.; Smirnova, L. A.; Petrov, V. I.; Shabasheva, I. G. (2002). Pharmacokinetics of rhythmidazol upon single intravenous administration. Eksperimental’naya i Klinicheskaya Farmakologiya 65(3), 57–61.

    CAS  Google Scholar 

  35. Beaumont, K.; Harper, A.; Smith, D. A.; Bennett, J. (2000). The role of P-glycoprotein in determining the oral absorption and clearance of the NK2 antagonist, UK-224,671. Eur J Pharm Sei 12(1), 41–50.

    Article  CAS  Google Scholar 

  36. Sukbuntherng, J; Cropp, G; Hannah, A; Wagner, G S.; Shawver, L K.; Antonian, L (2001). Pharmacokinetics and interspecies scaling of a novel VEGF receptor inhibitor, SU5416. J Pharm and Pharmacol 53(12), 1629–1636.

    Article  CAS  Google Scholar 

  37. Iavarone, L.; Hoke, J.F.; Bottacini, M.; Barnaby, R.; Preston, G. C. (1999). First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol 39(6), 560–566.

    Article  CAS  PubMed  Google Scholar 

  38. Mahmood, I. (1998). Interspecies scaling: Predicting volumes, mean residence time and elimination half-life. Some suggestions. J Pharm Pharmacol 50, 493–499.

    CAS  PubMed  Google Scholar 

  39. Bachmann, K; Pardoe, D; White, D. (1996) Scaling basic toxicokinetic parameters from rat to human. Environ Health Perspect 104(4), 400–407.

    Article  CAS  PubMed  Google Scholar 

  40. Bachmann, K. (1989). Predicting toxicokinetic parameters in humans from toxicokinetic data acquired from three small mammalian species. J Appl Toxicol 9(5), 331–8.

    Article  CAS  PubMed  Google Scholar 

  41. Vo_eh, S.; Schmidlin, O.; Taeschner, W. (1989). Pharmacokinetic drug Data. In: Clinical Pharmacokinetic Drug Data Handbook 1989. ADIS Press Limited, New Zealand, p. 1–38.

    Google Scholar 

  42. Travis, C. C; White, Robin, K.; Ward, Richard, C. (1990). Interspecies extrapolation of pharmacokinetics. J Theor Biol, 142(3), 285–304.

    Article  CAS  PubMed  Google Scholar 

  43. Fan, A.; Howd, R.; Davis, B. (1995). Risk assessment of environmental chemicals. Ann Rev Pharmacol Toxicol, 35, 341–68.

    Article  CAS  Google Scholar 

  44. Sanford, B., 1997. In: James Swarbrick (ed.) Pharmaceutical statistics: practical and clinical applications. Marcel Dekker Inc. New York, p. 17.

    Google Scholar 

  45. Sietsema, W K. (1989). The absolute oral bioavailability of selected drugs. Int J Clin Pharmacol Ther Toxicol 27(4), 179–211.

    CAS  PubMed  Google Scholar 

  46. Chiou, W. L.; Buehler, P W. (2002). Comparison of Oral Absorption and Bioavailability of Drugs Between Monkey and Human. Pharm Res 19(6), 868–874.

    Article  CAS  PubMed  Google Scholar 

  47. Mahmood, I. (2000). Can absolute oral bioavailability in humans be predicted from animals? A comparison of allometry and different indirect methods. Drug Metab Drug Int 16(2), 143–155.

    CAS  Google Scholar 

  48. Chiou, W. L.; Barve, A. (1998). Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res 5(11), 1792–1795.

    Article  Google Scholar 

  49. Chiou, W. L.; Ma, C; Chung, S. M.; Wu, T. C; Jeong, H. Y. (2000). Similarity in the linear and non-linear oral absorption of drugs between human and rat. Inter J Clin Pharmacol Ther 38(11), 532–539.

    CAS  Google Scholar 

  50. Chiou, W. L.; Jeong, Hyun, Y.; Chung, Sang, M.; Wu, Ta, C. (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(2), 135–140.

    Article  CAS  PubMed  Google Scholar 

  51. Amidon, G. L.; Sinko, P. J.; Fleisher, D (1988). Estimating human oral fraction dose absorbed: a correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm Res 5(10), 651–4.

    Article  CAS  PubMed  Google Scholar 

  52. Mahmood, I. (1998). Interspecies scaling of renally secreted drugs. Life Sei. 63, 2365–2371.

    Article  CAS  Google Scholar 

  53. Sarver, J G.; White, D; Erhardt, P; Bachmann, K. (1997). Estimating xenobiotic half-lives in humans from rat data: influence of log P. Environ Health Perspect 105(11); 1204–1209.

    Article  CAS  PubMed  Google Scholar 

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Caldwell, G.W., Masucci, J.A., Yan, Z. et al. Allometric scaling of pharmacokinetic parameters in drug discovery: Can human CL, Vss and t1/2 be predicted fromin-vivo rat data?. European Journal of Drug Metabolism and Pharmacokinetics 29, 133–143 (2004). https://doi.org/10.1007/BF03190588

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