Pharmacometrics in pediatric drug development and rational dosage

Abstract

Abstract: This article provides a comprehensive overview of key issues related to pediatric drug development and rational dosing guidance in pediatrics with an emphasis on how pharmacometrics can improve the efficiency and productivity of pediatric trials. The pharmacokinetics (PK) and pharmacodynamics (PD) of drugs are often different between adult and pediatric populationns which necessitate specific studies in children.The aims of this review are to discuss a number of recent methodological developments of modeling and simulation that facilitate the evaluation of drugs in pediatrics.Specific focus has been placed on addressing the key issues of PK/PD scaling, sparse sampling, colinearity, covariate evaluation, dose optimization for trial design and label, modeling strategies and validation approaches.The features and potent ial advantages of Bayesian hierarchical model, physiology-based PK models, and K-PD models are also presented.

Key words: Pediatric trials, Pharmacometrics, Sparse sampling, Modeling and simulation, Bayesian hierarchical model

SHI Jun, Jeffrey S .Barrett. Pharmacometrics in pediatric drug development and rational dosage[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(1): 1-10.

References

[1] Ande rson BJ, Ho lfo rd NH. Mechanism-based concepts of size and maturity in pharmaco kinetics[J]. Annu Rev Pharmacol Toxicol, 2008, 48: 303-332.
[2] Shi J, Ludden TM, Melikian AP, et al. Population pharmacokinetics and pharmaco dynamics of sotalolin pediatric patients with supraventricular or ventricular tachy arrhythmia[J]. J Pharmacokinet Pharmacodyn, 2001, 28(6): 555-575.
[3] Meibohm B, Läer S, Panetta JC, et al. Population pharmacokinetic studies in pediatrics: issues in design and analysis[J]. AAPS J, 2005, 7(2): E475-487.
[4] Shi J, Kovacs SJ, Wang Y, et al. Population pharmacokinetics of the active metabolite of leflunomide in pediatric subjects with poly articular course juvenile rheumatoid arthritis[J]. J Pharmacokinet Pharmacodyn, 2005, 32(3/ 4): 419-439.
[5] Tod M, Jullien V, Po ns G. Facilitation of drug evaluatio n in children by population methods and modeling[J]. Clin Pharmacokinet, 2008, 47(4): 231-243.
[6] Mager DE, Jusko WJ. Development of translational pharmacokinetic-pharmacodynamic models[J]. Clin Pharmacol Ther, 2008, 83(6): 909-912.
[7] http:// www. pfim. biostat. fr/ index. htm?to=download. php
[8] Bonate PL. Pharmacokinetic-Pharmacodynamic Modeling and Simulation[M]. New York: Springer, 2005.
[9] Harrell FE. Regression modeling strategies: With applications to linear models, lo gistic regression, and survival analysis[M]. New York: Springer-Verlag, 2001.
[10] Burhham KP, Ander son DR. Model selection and multimodel inference: A practical information-theoretic approach [M]. New York: Springer-Verlag, 2002.
[11] Gastonguay M, Gibiansky E, Gibiansky L, et al. Optimizing a Bayesian Do se-Adjustment Scheme for a Pediatric Trial: A Simulation Study, in Simulation for Designing Clinical Trials, A Pharmaco kinetic-Pharmacodynamic Modeling Perspective[M] // Kimko H C, Duffull SB, Marcel Dekker. Drug s and the Pharmaceutical Sciences Series. New York, 2003.
[12]http:// www. mrc-su. cam. ac. uk/bugs/winbugs/contents. shtml
[13] FDA Population pharmaco kinetics guidance for industry[S]. 1999.
[14] Karlsson M O, Savic RM. Diagno sing model diagnostics[J]. Clin Pharmacol Ther, 2007, 82(1): 17-20
[15] Benjamin DK Jr, Smith PB, Jadhav P, et al. Pediatric antihyper tensive trial failures: analysis of endpoints and do serange[J]. Hyper tension, 2008, 51(4): 834-840.
[16] Shi J. Application of PK/PD Modeling and Clinical Trial Simulation in Pediatrics-Bridging the Know ledgeGap[C]. American Society for Clinical Pharmacology Annual Meeting, 2009.
[17] Bragg P, Fisher DM, Shi J, et al. Comparison of twitch de pressio n of the adductor pollicis and the respiratory muscles. Pharmaco dynamic modeling without plasma concentrations[J]. Anesthesiology, 1994, 80(2): 310-319.
[18] Jacqmin P, Snoeck E, van Schaick EA, et al. Modelling response time pro files in the absence of drug concentrations: definition and performance evaluation of the K-PD model[J]. J Pharmacokinet Pharmacodyn, 2007, 34(1): 57-85.
[19] Price PS, Conolly RB, Chaisson CF, et al. Modeling interindividual variation in physiological factors used in PBPK models of humans[J]. CritRev Toxicol, 2003, 33(5): 469-503.
[20] Yang F, Tong X, Mc Carver DG, et al. Population based analysis of methadone distribution and metabolism using an age-dependent physiologically based pharmacokinetic model[J]. J Pharmacokinet Pharmacodyn, 2006, 33(4): 485-518.
[21]http://www. simcy p. com/