Abstract
Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.
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Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364–382.
Goran MI, Ball GD, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab. 2003;88(4):1417–1427.
Krakoff J, Hanson RL, Kobes S, Knowler WC. Comparison of the effect of plasma glucose concentrations on microvascular disease between Pima Indian youths and adults. Diabetes Care. 2001;24(6):1023–1028.
Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M. Type 2 diabetes in the young: the evolving epidemic: the International Diabetes Federation consensus workshop. Diabetes Care. 2004;27(7):1798–1811.
Pinhas-Hamiel O, Zeitler P. Clinical presentation and treatment of type 2 diabetes in children. Pediatr Diabetes. 2007;8(suppl 9):16–27.
World Health Organization. Diabetes Fact Sheet. Geneva, Switzerland: World Health Organization; March 2013.
Imperatore G, Boyle JP, Thompson TJ, et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care. 2012;35(12):2515–2520.
Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and beta-cell function in TODAY. Diabetes Care. 2013;36(6):1749–1757.
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–2443.
Zeitler P, Hirst K, Pyle L, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247–2256.
Zee P, Portman R. Paediatric type 2 diabetes mellitus meeting trial recruitment issues—a company perspective. In: EMA Workshop on Paediatric Investigation Plans in Type-2 Diabetes Mellitus. London, UK: European Medicines Agency; 2013.
US Food and Drug Administration. Specific Requirements on Content and Format of Labeling for Human Prescription Drugs: Revision of “Pediatric Use” Subsection in the Labeling: Final Rule, Federal Register. Silver Spring, MD: US Food and Drug Administration; 1994.
European Medicines Agency. Concept Paper on Extrapolation of Efficacy and Safety in Medicine Development. London, UK: European Medicines Agency; 2012.
Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242–e1249.
Tamborlane W. T2D in children and adolescents. In: EMA Workshop on Paediatric Investigation Plans in Type-2 Diabetes Mellitus. London, UK: European Medicines Agency; 2013.
Tamborlane WV, Klingensmith G. Crisis in care: limited treatment options for type 2 diabetes in adolescents and youth. Diabetes Care. 2013;36(6):1777–1778.
Vaidyanathan J, Choe S, Sahajwalla CG. Type 2 diabetes in pediatrics and adults: thoughts from a clinical pharmacology perspective. J Pharm Sci. 2012;101(5):1659–1671.
Bellanti F, Della Pasqua O. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol. 2011;67(suppl 1):75–86.
Jadhav PR, Kern SE. The need for modeling and simulation to design clinical investigations in children. J Clin Pharmacol. 2010;50(suppl 9):121S–129S.
Jadhav PR, Zhang J, Gobburu JV. Leveraging prior quantitative knowledge in guiding pediatric drug development: a case study. Pharm Stat. 2009;8(3):216–224.
Leong R, Vieira ML, Zhao P, et al. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther. 2012;91(5):926–931.
Manolis E, Osman TE, Herold R, et al. Role of modeling and simulation in pediatric investigation plans. Paediatr Anaesth. 2011;21(3):214–221.
Salazar DE, Song SH, Shi J, et al. The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects. Clin Pharmacol Ther. 2012;91(2):250–256.
Hazan L, Hernandez Rodriguez OA, Bhorat AE, Miyazaki K, Tao B, Heyrman R. A double-blind, dose-response study of the efficacy and safety of olmesartan medoxomil in children and adolescents with hypertension. Hypertension. 2010;55(6):1323–1330.
Nisal K, Kela R, Khunti K, Davies MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Med. 2012;10:152.
Gibbs JP, Fredrickson J, Barbee T, et al. Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results. J Clin Pharmacol. 2012;52(10):1494–1505.
Johnson TN, Rostami-Hodjegan A. Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice. Paediatr Anaesth. 2011;21(3):291–301.
van den Anker JN, Schwab M, Kearns GL. Developmental pharmacokinetics. Handb Exp Pharmacol. 2011;205:51–75.
Fraser IP, Neufeld N, Fox LA, et al. Pharmacokinetics and pharmacodynamics of sitagliptin in adolescents with type 2 diabetes. Paper presented at: American Diabetes Association, 73rd Scientific Sessions; 2013; Chicago, IL.
Schoenfeld DA, Hui Z, Finkelstein DM. Bayesian design using adult data to augment pediatric trials. Clin Trials. 2009;6(4):297–304.
Lai TL, Lavori PW, Shih MC. Adaptive trial designs. Annu Rev Pharmacol Toxicol. 2012;52:101–110.
Slikker W Jr., Young JF, Corley RA, et al. Improving predictive modeling in pediatric drug development: pharmacokinetics, pharmacodynamics, and mechanistic modeling. Ann N Y Acad Sci. 2005;1053:505–518.
Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–956.
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Leil, T.A., Zee, P., Suryawanshi, S. et al. Quantitative Extrapolation: An Approach to Validation of Adult Drug Efficacy in Pediatric Subjects. Ther Innov Regul Sci 47, 557–565 (2013). https://doi.org/10.1177/2168479013500286
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DOI: https://doi.org/10.1177/2168479013500286