Clinical trials simulation in drug development

Abstract

Abstract: Clinical trial simulation is playing more and more important role in new drug development, making the drug development more efficient and informative. Clinical trial simulation can be viewed as the abstraction of the clinical trial process. It is used to investigate assumptions and to influence trial design in order to maximize the amount of information gained in drug development. Simulation can be used for modeling variability, estimating the impact of operational factors, evaluating assumptions, comparing trial designs, discriminating between competing drugs. In this review, we describe the motivations and history, general methodology and some examples of clinical trial simulation, including a brief description of current software available for performing such simulations, and finally our view of the current and future impact and directions for this powerful technology in drug development. Simulation is applicable to many areas of the clinical trial process. The focus here centers on the use of simulation with models based upon the pharmacokinetic-pharmacodynamic relationship that reflect the disposition and effect of drugs as observed in clinical trials.

Key words: Clinical trial simulation, Modeling & simulation, Mode-based drug development

CLC Number:

R969

HUANG Ji-han, HUANG Xiao-hui, LI Lu-jin, WANG Qin, WANG Kun, ZHENG Qing-shan. Clinical trials simulation in drug development[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(6): 691-699.

References

[1] Pascal Girard. Clinical Trial Simulation: A Tool for Understanding Study Failures and Preventing Them[J]. Basic Clin Pharmacol Toxicol, 2005, 96(3): 228-234.
[2] Dokoumetzidis A, Valsami G, Macheras P. Modelling and simulation in drug absorption processes[J]. Xenobiotica,2007,37(10/11):1052-1065.
[3] Hale MD, Gillespie WR, Gupta, et al. Clinical trial simulation: streamlining your drug development process[J]. Appl Clin Trials, 1996,5: 35-40 .
[4] Holford NH, Kimko HC, Monteleone JP, et al. Simulation of clinical trials[J]. Annu Rev Pharmacol Toxicol,2000, 40:209-234.
[5] Kimko H, Duffull S. Simulation for designing clinical trials : A Pharmacokinetic-pharmacodynamic modeling perspective[M]. New York : Marcel Dekker, 2003.
[6] 黄晓晖, 史军,李俊,等.药代动力学和药效动力学中数学建模与模拟的基本原理(1) [J]. 中国临床药理学与治疗学,2007, 12 (1) :82-89.
[7] 黄晓晖,史军,李俊,等. 药代动力学和药效动力学中数学建模与模拟的基本原理( 2) [J]. 中国临床药理学与治疗学,2007,12 (3) :334-341.
[8] US Department of Health and Human Services, Food and Drug Administration. Innovation or stagnation? Challenge and opportunity on the critical path to new medical products [EB/OL]. [2010-04-10]. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf(2004).
[9] Lalonde RL, Kowalski KG, Hutmacher MM, et al, Model-based drug development[J]. Clin Pharmacol Ther, 2007,82(1):21-32.
[10] 黄晓晖,谢海棠,史军,等. 现代定量药理学的研究进展及展望[J]. 中国临床药理学与治疗学, 2009, 14(6): 601-612.
[11] Sun H, Fadiran EO, Jones CD, et al. Population pharmacokinetics. A regulatory perspective[J]. Clin Pharmacokinet, 1999,37(1):41-58.
[12] Lavé T, Parrott N, Grimm HP, et al. Challenges and opportunities with modelling and simulation in drug discovery and drug development[J]. Xenobiotica, 2007,37(10/11):1295-1310.
[13] Holford NH, Hale M, Kimko HC, et al. Simulation in Drug Development: Good Practices[EB/OL]. (1999-07-23). http://bts.ucsf.edu/cdds/research/sddgp.php.
[14] Zhang L, Sinha V, Forgue ST, et al. Model-based drug development: the road to quantitative pharmacology[J]. J Pharmacokinet Pharmacodyn,2006, 33(3):369-393.
[15] Grasela TH, Fiedler-Kelly J, Walawander CA, et al. Challenges in the transition to model-based development[J]. AAPS J, 2005,7(2):E488-495.
[16] Pharsight Corporation. Trial Simulator user's guide (V2.2. 2) [ S]. 2006.
[17] Mahmood I, Balian JD. The pharmacokinetic principles behind scaling from preclinical results to phase I protocols[J]. Clin Pharmacokinet, 1999, 36(1):1-11.
[18] Aarons L, Karlsson MO, Mentré F, et al.Role of modelling and simulation in Phase I drug development[J]. Eur J Pharm Sci, 2001,13(2):115-122.
[19] Pereira Luis M. Critical Considerations about Clinical Trials Simulation[J]. Int J Pharm Med, 2006, 20(1): 1-15.
[20] Weiner D. Modeling, Simulation, and the Critical Path[J]. Drug Discov Dev, 2006, 9(12): 54.
[21] Rooney KF, Snoeck E, Watson PH. Modelling and simulation in clinical drug development[J]. Drug Discov Today,2001,6(15):802-806.
[22] Rajman I. PK/PD modelling and simulations: utility in drug development[J]. Drug Discov Today. 2008,13(7/8):341-346.
[23] Sheiner LB. Learning versus confirming in clinical drug development[J]. Clin Pharmacol Ther, 1997,61(3):275-291.
[24] Mandema JW, Stanski DR. Population pharmacodynamic model for ketorolac analgesia[J]. Clin Pharmacol Ther,1996, 60(6):619-635.
[25] Minto CF, Schnider TW, Egan TD,et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development [J]. Anesthesiology, 1997,86(1):10-23.
[26] Kodlin D, Cohn I Jr. Simulation experiments of tumor measurement in clinical trials[J]. Cancer Treat Rep, 1978, 62(12):2077-2083.
[27] Skolnik JM, Barrett JS, Jayaraman B, et al. Shortening the timeline of pediatric phase I trials: the rolling six design [J]. J Clin Oncol, 2008,26(2):190-195.
[28] Fetterly GJ, Grasela TH, Sherman JW, et al. Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel[J]. Clin Cancer Res, 2008,14(18):5856-5863.
[29] Lockwood P, Ewy W, Hermann D, et al. Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease[J]. Pharm Res, 2006, 23(9):2050-2059.
[30] Lockwood PA, Cook JA, Ewy WE, et al. The use of clinical trial simulation to support dose selection: application to development of a new treatment for chronic neuropathic pain[J]. Pharm Res, 2003,20(11):1752-1759.
[31] Kowalski KG, Olson S, Remmers AE, et al. Modeling and simulation to support dose selection and clinical development of SC-75416, a selective COX-2 inhibitor for the treatment of acute and chronic pain[J]. Clin Pharmacol Ther, 2008,83(6):857-866.
[32] Rohatagi S, Carrothers TJ, Jin J, et al. Model-based development of a PPAR-gamma agonist, rivoglitazone, to aid dose selection and optimize clinical trial designs[J]. J Clin Pharmacol, 2008,48(12):1420-1429.
[33] Veyrat-Follet C, Bruno R, Olivares R, et al. clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization[J]. Clin Pharmacol Ther, 2000,68(6):677-687.
[34] Rosario MC, Poland B, Sullivan J, et al. A pharmacokinetic-pharmacodynamic model to optimize the phase IIa development program of maraviroc[J]. J Acquir Immune Defic Syndr, 2006,42(2):183-191.
[35] Roy A, Mould DR, Wang XF, et al. Modeling and simulation of abatacept exposure and interleukin-6 response in support of recommended doses for rheumatoid arthritis[J]. J Clin Pharmacol, 2007, 47(11):1408-1420.
[36] Chabaud S, Girard P, Nony P, et al. Clinical trial simulation using therapeutic effect modeling: application to ivabradine efficacy in patients with angina pectoris[J]. J Pharmacokinet Pharmacodyn, 2002,29(4):339-363.
[37] Gruwez B, Poirier MF, Dauphin A, et al. A kinetic-pharmacodynamic model for clinical trial simulation of antidepressant action: Application to clomipramine-lithium interaction[J]. Contemp Clin Trials, 2007,28(3):276-287.
[38] Bonate PL. Clinical trial simulation in drug development [J]. Pharm Res, 2000,17(3): 252-256.