Abstract
Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK- or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.
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REFERENCES
Contrera JF, Matthews EJ, Kruhlak NL, Benz RD. Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose. Regul Toxicol Pharmacol. 2004;40(3):185–206.
FDA. Guidance for industry-Estimating the maximum safe dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville. 2005.
Mahmood I. Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development. Adv Drug Deliv Rev. 2007;59(11):1177–92.
Reigner BG, Williams PE, Patel IH, Steimer JL, Peck C, van Brummelen P. An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche. Clin Pharmacokinet. 1997;33(2):142–52.
Reigner BG, Blesch KS. Estimating the starting dose for entry into humans: principles and practice. Eur J Clin Pharmacol. 2002;57(12):835–45.
Tang H, Mayersohn M. A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry. J Pharm Sci. 2006;95(8):1783–99.
Mahmood I. Response to the comments on the commentary ‘Prediction of absolute bioavailability for drugs using oral and renal clearance following a single oral dose: a critical view’. Biopharm Drug Dispos. 1998;19(7):483–4.
Lave T, Dupin S, Schmitt C, Chou RC, Jaeck D, Coassolo P. 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(5):584–90.
Goteti K, Brassil PJ, Good SS, Garner CE. Estimation of human drug clearance using multiexponential techniques. J Clin Pharmacol. 2008;48(10):1226–36.
Tang H, Mayersohn M. A novel model for prediction of human drug clearance by allometric scaling. Drug Metab Dispos. 2005;33(9):1297–303.
Tang H, Hussain A, Leal M, Mayersohn M, Fluhler E. Interspecies prediction of human drug clearance based on scaling data from one or two animal species. Drug Metab Dispos. 2007;35(10):1886–93.
Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther. 1997;283(1):46–58.
Ito K, Houston JB. Prediction of human drug clearance from in vitro and preclinical data using physiologically based and empirical approaches. Pharm Res. 2005;22(1):103–12.
Lave T, Coassolo P, Reigner B. Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations. Clin Pharmacokinet. 1999;36(3):211–31.
Hosea NA, Collard WT, Cole S, Maurer TS, Fang RX, Jones H, et al. Prediction of human pharmacokinetics from preclinical information: comparative accuracy of quantitative prediction approaches. J Clin Pharmacol. 2009;49(5):513–33.
Lowe PJ, Hijazi Y, Luttringer O, Yin H, Sarangapani R, Howard D. On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development. Xenobiotica. 2007;37(10–11):1331–54.
Fagerholm U. Prediction of human pharmacokinetics—evaluation of methods for prediction of volume of distribution. J Pharm Pharmacol. 2007;59(9):1181–90.
Fagerholm U. Prediction of human pharmacokinetics—evaluation of methods for prediction of hepatic metabolic clearance. J Pharm Pharmacol. 2007;59(6):803–28.
Fagerholm U. Prediction of human pharmacokinetics-biliary and intestinal clearance and enterohepatic circulation. J Pharm Pharmacol. 2008;60(5):535–42.
Fagerholm U. Prediction of human pharmacokinetics—renal metabolic and excretion clearance. J Pharm Pharmacol. 2007;59(11):1463–71.
Ghibellini G, Leslie EM, Brouwer KL. Methods to evaluate biliary excretion of drugs in humans: an updated review. Mol Pharm. 2006;3(3):198–211.
Houston JB, Galetin A. Progress towards prediction of human pharmacokinetic parameters from in vitro technologies. Drug Metab Rev. 2003;35(4):393–415.
Chiba M, Ishii Y, Sugiyama Y. Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J. 2009;11(2):262–76.
Sharma V, McNeill JH. To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol. 2009;157(6):907–21.
European Medicines Agency. Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. 2007.
Mahmood I, Green MD, Fisher JE. Selection of the first-time dose in humans: comparison of different approaches based on interspecies scaling of clearance. J Clin Pharmacol. 2003;43(7):692–7.
Iavarone L, Hoke JF, Bottacini M, Barnaby R, Preston GC. First time in human for GV196771: interspecies scaling applied on dose selection. J Clin Pharmacol. 1999;39(6):560–6.
Agoram BM. Use of pharmacokinetic/pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. Br J Clin Pharmacol. 2009;67(2):153–60.
Heimbach T, Lakshminarayana SB, Hu W, He H. Practical anticipation of human efficacious doses and pharmacokinetics using in vitro and preclinical in vivo data. AAPS J. 2009;11(3):602–14.
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.
Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem Biophys Res Commun. 1991;175(3):880–5.
Rubas W, Cromwell ME, Shahrokh Z, Villagran J, Nguyen TN, Wellton M, et al. Flux measurements across Caco-2 monolayers may predict transport in human large intestinal tissue. J Pharm Sci. 1996;85(2):165–9.
Muller PY, Brennan FR. Safety assessment and dose selection for first-in-human clinical trials with immunomodulatory monoclonal antibodies. Clin Pharmacol Ther. 2009;85(3):247–58.
Fagerholm U. The role of permeability in drug ADME/PK, interactions and toxicity—presentation of a permeability-based classification system (PCS) for prediction of ADME/PK in humans. Pharm Res. 2008;25(3):625–38.
Dokoumetzidis A, Kosmidis K, Argyrakis P, Macheras P. Modeling and Monte Carlo simulations in oral drug absorption. Basic Clin Pharmacol Toxicol. 2005;96(3):200–5.
Tang H, Mayersohn M. Utility of the coefficient of determination (r2) in assessing the accuracy of interspecies allometric predictions: illumination or illusion? Drug Metab Dispos. 2007;35(12):2139–42.
Sinha VK, De Buck SS, Fenu LA, Smit JW, Nijsen M, Gilissen RA, et al. Predicting oral clearance in humans: how close can we get with allometry? Clin Pharmacokinet. 2008;47(1):35–45.
Mahmood I. Interspecies scaling: role of protein binding in the prediction of clearance from animals to humans. J Clin Pharmacol. 2000;40(12 Pt 2):1439–46.
Boxenbaum H, Fertig JB. Scaling of antipyrine intrinsic clearance of unbound drug in 15 mammalian species. Eur J Drug Metab Pharmacokinet. 1984;9(2):177–83.
Mahmood I. Prediction of human drug clearance from animal data: application of the rule of exponents and ‘fu Corrected Intercept Method’ (FCIM). J Pharm Sci. 2006;95(8):1810–21.
Stoner CL, Cleton A, Johnson K, Oh DM, Hallak H, Brodfuehrer J, et al. Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery. Int J Pharm. 2004;269(1):241–9.
Nagilla R, Ward KW. 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. 2004;93(10):2522–34.
Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol. 1994;47(9):1469–79.
Mahmood I. Interspecies scaling of biliary excreted drugs: a comparison of several methods. J Pharm Sci. 2005;94(4):883–92.
Lave T, Coassolo P, Ubeaud G, Brandt R, Schmitt C, Dupin S, et al. Interspecies scaling of bosentan, a new endothelin receptor antagonist and integration of in vitro data into allometric scaling. Pharm Res. 1996;13(1):97–101.
Obach RS. The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Devel. 2001;4(1):36–44.
Shibata Y, Takahashi H, Chiba M, Ishii Y. Prediction of hepatic clearance and availability by cryopreserved human hepatocytes: an application of serum incubation method. Drug Metab Dispos. 2002;30(8):892–6.
Goteti K, Garner CE, Mahmood I. Prediction of human drug clearance from two species: a comparison of several allometric methods. J Pharm Sci. 2010;99(3):1601–13.
Ward KW, Smith BR. A comprehensive quantitative and qualitative evaluation of extrapolation of intravenous pharmacokinetic parameters from rat, dog, and monkey to humans. II. Volume of distribution and mean residence time. Drug Metab Dispos. 2004;32(6):612–9.
Mahmood I. Role of fixed coefficients and exponents in the prediction of human drug clearance: how accurate are the predictions from one or two species? J Pharm Sci. 2009;98(7):2472–93.
Charman WN, Porter CJ, Mithani S, Dressman JB. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci. 1997;86(3):269–82.
Tang H, Mayersohn M. On the observed large interspecies overprediction of human clearance (“vertical allometry”) of UCN-01: further support for a proposed model based on plasma protein binding. J Clin Pharmacol. 2006;46(4):398–400.
Hakooz N, Ito K, Rawden H, Gill H, Lemmers L, Boobis AR, et al. Determination of a human hepatic microsomal scaling factor for predicting in vivo drug clearance. Pharm Res. 2006;23(3):533–9.
Ito K, Houston JB. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes. Pharm Res. 2004;21(5):785–92.
Niro R, Byers JP, Fournier RL, Bachmann K. Application of a convective-dispersion model to predict in vivo hepatic clearance from in vitro measurements utilizing cryopreserved human hepatocytes. Curr Drug Metab. 2003;4(5):357–69.
Ashforth EI, Carlile DJ, Chenery R, Houston JB. Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data. J Pharmacol Exp Ther. 1995;274(2):761–6.
Soars MG, Burchell B, Riley RJ. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther. 2002;301(1):382–90.
Brown HS, Griffin M, Houston JB. Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab Dispos. 2007;35(2):293–301.
Sun D, Yu LX, Hussain MA, Wall DA, Smith RL, Amidon GL. In vitro testing of drug absorption for drug ‘developability’ assessment: forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel. 2004;7(1):75–85.
Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab Dispos. 2001;29(10):1316–24.
Naritomi Y, Terashita S, Kagayama A, Sugiyama Y. Utility of hepatocytes in predicting drug metabolism: comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro. Drug Metab Dispos. 2003;31(5):580–8.
Lave T, Dupin S, Schmitt C, Valles B, Ubeaud G, Chou RC, et al. The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans. Pharm Res. 1997;14(2):152–5.
Zuegge J, Schneider G, Coassolo P, Lave T. Prediction of hepatic metabolic clearance: comparison and assessment of prediction models. Clin Pharmacokinet. 2001;40(7):553–63.
Fagerholm U. Prediction of human pharmacokinetics—improving microsome-based predictions of hepatic metabolic clearance. J Pharm Pharmacol. 2007;59(10):1427–31.
Obach RS. 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. 1999;27(11):1350–9.
Stringer R, Nicklin PL, Houston JB. Reliability of human cryopreserved hepatocytes and liver microsomes as in vitro systems to predict metabolic clearance. Xenobiotica. 2008;38(10):1313–29.
Skaggs SM, Foti RS, Fisher MB. A streamlined method to predict hepatic clearance using human liver microsomes in the presence of human plasma. J Pharmacol Toxicol Methods. 2006;53(3):284–90.
Stringer RA, Strain-Damerell C, Nicklin P, Houston JB. Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab Dispos. 2009;37(5):1025–34.
Galetin A, Brown C, Hallifax D, Ito K, Houston JB. Utility of recombinant enzyme kinetics in prediction of human clearance: impact of variability, CYP3A5, and CYP2C19 on CYP3A4 probe substrates. Drug Metab Dispos. 2004;32(12):1411–20.
Kilford PJ, Stringer R, Sohal B, Houston JB, Galetin A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab Dispos. 2009;37(1):82–9.
Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Prediction of intestinal first-pass drug metabolism. Curr Drug Metab. 2007;8(7):676–84.
Wajima T, Fukumura K, Yano Y, Oguma T. Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis. J Pharm Sci. 2002;91(12):2489–99.
Nikolic K, Agababa D. Prediction of hepatic microsomal intrinsic clearance and human clearance values for drugs. J Mol Graph Model. 2009;28(3):245–52.
Dokoumetzidis A, Kalantzi L, Fotaki N. Predictive models for oral drug absorption: from in silico methods to integrated dynamical models. Expert Opin Drug Metab Toxicol. 2007;3(4):491–505.
Obach RS, Lombardo F, Waters NJ. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dispos. 2008;36(7):1385–405.
Badhan R, Penny J, Galetin A, Houston JB. Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption. J Pharm Sci. 2009;98(6):2180–97.
Kesisoglou F, Wu Y. Understanding the effect of API properties on bioavailability through absorption modeling. AAPS J. 2008;10(4):516–25.
Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—fact or myth. Pharm Res. 1997;14(6):763–6.
Sugano K, Hamada H, Machida M, Ushio H, Saitoh K, Terada K. Optimized conditions of bio-mimetic artificial membrane permeation assay. Int J Pharm. 2001;228(1–2):181–8.
Pidgeon C, Ong S, Liu H, Qiu X, Pidgeon M, Dantzig AH, et al. IAM chromatography: an in vitro screen for predicting drug membrane permeability. J Med Chem. 1995;38(4):590–4.
Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41(7):1007–10.
Zhu C, Jiang L, Chen TM, Hwang KK. A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur J Med Chem. 2002;37(5):399–407.
Kotecha J, Shah S, Rathod I, Subbaiah G. Relationship between immobilized artificial membrane chromatographic retention and human oral absorption of structurally diverse drugs. Int J Pharm. 2007;333(1–2):127–35.
Cao X, Gibbs ST, Fang L, Miller HA, Landowski CP, Shin HC, et al. Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm Res. 2006;23(8):1675–86.
Akabane T, Tabata K, Kadono K, Sakuda S, Terashita S, Teramura T. A comparison of pharmacokinetics between humans and monkeys. Drug Metab Dispos. 2010;38(2):308–16.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23(1–3):3–25.
Andrews CW, Bennett L, Yu LX. Predicting human oral bioavailability of a compound: development of a novel quantitative structure-bioavailability relationship. Pharm Res. 2000;17(6):639–44.
Yoshida F, Topliss JG. QSAR model for drug human oral bioavailability. J Med Chem. 2000;43(13):2575–85.
Dedrick R, Bischoff KB, Zaharko DS. Interspecies correlation of plasma concentration history of methotrexate (NSC-740). Cancer Chemother Rep. 1970;54(2):95–101.
Mahmood I, Yuan R. A comparative study of allometric scaling with plasma concentrations predicted by species-invariant time methods. Biopharm Drug Dispos. 1999;20(3):137–44.
Wajima T, Yano Y, Fukumura K, Oguma T. Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles. J Pharm Sci. 2004;93(7):1890–900.
Fura A, Vyas V, Humphreys W, Chimalokonda A, Rodrigues D. Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compounds. Biopharm Drug Dispos. 2008;29(8):455–68.
Gibson CR, Bergman A, Lu P, Kesisoglou F, Denney WS, Mulrooney E. Prediction of phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling. Xenobiotica. 2009;39(9):637–48.
Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J. On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. Basic Clin Pharmacol Toxicol. 2010;106(3):195–209.
De Buck SS, Sinha VK, Fenu LA, Nijsen MJ, Mackie CE, Gilissen RA. Prediction of human pharmacokinetics using physiologically based modeling: a retrospective analysis of 26 clinically tested drugs. Drug Metab Dispos. 2007;35(10):1766–80.
Jones HM, Parrott N, Jorga K, Lave T. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet. 2006;45(5):511–42.
Schneider G, Coassolo P, Lave T. Combining in vitro and in vivo pharmacokinetic data for prediction of hepatic drug clearance in humans by artificial neural networks and multivariate statistical techniques. J Med Chem. 1999;42(25):5072–6.
Mohutsky MA, Chien JY, Ring BJ, Wrighton SA. Predictions of the in vivo clearance of drugs from rate of loss using human liver microsomes for phase I and phase II biotransformations. Pharm Res. 2006;23(4):654–62.
Huang C, Zheng M, Yang Z, Rodrigues AD, Marathe P. Projection of exposure and efficacious dose prior to first-in-human studies: how successful have we been? Pharm Res. 2008;25(4):713–26.
ACKNOWLEDGMENTS
This work was partially supported by the National Institutes of Health (RO1 CA120023); University of Michigan Cancer Center Research Grant (Munn); and University of Michigan Cancer Center Core Grant to DS.
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Zou, P., Yu, Y., Zheng, N. et al. Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation. AAPS J 14, 262–281 (2012). https://doi.org/10.1208/s12248-012-9332-y
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DOI: https://doi.org/10.1208/s12248-012-9332-y