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Pharmacometrics in Pediatrics

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Book cover Applied Pharmacometrics

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 14))

Abstract

Pharmacometric approaches applied to the design and analysis of pediatric clinical pharmacology trials are essential for providing informative dosing guidance in children. This chapter reviews the key questions that define the proper implementation of pharmacometrics in the study of pediatric populations, examines historical, current, and optimal dosing practices, examines various expressions of time indices which allow us to define developmental and maturation processes which impact drug clearance, and presents physiologic considerations for the developing child. Methods and examples of leveraging adult data to inform initial population-based pediatric pharmacokinetic/pharmacodynamics (PK/PD) models are examined as well as in silico approaches not reliant on adult data to guide pediatric PK projection are examined. Workflows for physiologically based PK (PBPK) approaches are discussed as well. Finally, a detailed case study of a modeling and simulation approach to guide the design of a prospective pediatric phase-II trial is presented. Hence, this chapter provides strong evidence and a practical approach to supporting pediatric research and development via pharmacometrically guided investigation.

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References

  • Alcorn J, McNamara PJ (2008) Using ontogeny information to build predictive models for drug elimination. Drug Discov Today 13(11–12):507–512

    Article  CAS  PubMed  Google Scholar 

  • Anderson BJ, Holford NH (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332

    Article  CAS  PubMed  Google Scholar 

  • Anderson GD, Lynn AM (2009) Optimizing pediatric dosing: a developmental pharmacologic approach. Pharmacotherapy 29(6):680–690

    Article  CAS  PubMed  Google Scholar 

  • Barker P, Nowak C, King K, Mosca R, Bove E, Goldberg C (2005) Risk factors for cerebrovascular events following Fontan palliation in patients with a functional single ventricle. Am J Cardiol 96:587–591

    Article  PubMed  Google Scholar 

  • Barrett JS, Mitchell LG, Patel D, Cox P, Vegh P, Castillo M, Massicotte P (2008a) A population-based analysis of dalteparin pharmacokinetics in pediatric patients at risk for thromboembolic events. J Clin Pharmacol 48(9):1107

    Google Scholar 

  • Barrett JS, Mondick JT, Narayan M, Vijayakumar K, Vijayakumar S (2008b) Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy. BMC Med Inform Decis Mak 8:6

    Google Scholar 

  • Barrett JS, Narayan M, Patel D, Zuppa AF, Adamson PC (2011) Prescribing habits and caregiver satisfaction with resources for dosing children: rationale for more informative dosing guidance. BMC Pediatr 11:25

    Article  PubMed Central  PubMed  Google Scholar 

  • Barrett JS, Della CAlberighiO, Laer S, Meibohm B (2012) Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther 92(1):40–49

    Article  CAS  PubMed  Google Scholar 

  • Belik J, Karpinka B, Hart DA (2000) Pulmonary and systemic vascular tissue collagen, growth factor, and cytokine gene expression in the rabbit. Can J Physiol Pharmacol 78(5):400–406

    Article  CAS  PubMed  Google Scholar 

  • Blake MJ, Castro L, Leeder JS, Kearns GL (2005) Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 10(2):123–138

    Article  PubMed  Google Scholar 

  • Clapp DW (2006) Developmental regulation of the immune system. Semin Perinatol 30(2):69–72

    Article  PubMed  Google Scholar 

  • Crom WR, de Graaf SS, Synold T, Uges DR, Bloemhof H, Rivera G, Christensen ML, Mahmoud H, Evans WE (1994) Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 125(4):642–649

    Article  CAS  PubMed  Google Scholar 

  • Dombrowsky E, Jayaraman B, Narayan M, Barrett JS (2011) Evaluating performance of a decision support system to improve methotrexate pharmacotherapy in children and young adults with cancer. Ther Drug Monit 33(1):99–107

    Article  PubMed Central  PubMed  Google Scholar 

  • Dorschner RA, Lin KH, Murakami M, Gallo RL (2003) Neonatal skin in mice and humans expresses increased levels of antimicrobial peptides: innate immunity during development of the adaptive response. Pediatr Res 53(4):566–572

    Article  CAS  PubMed  Google Scholar 

  • Edginton AN, Schmitt W, Voith B, Willmann S (2006a) A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet 45(7):683–704

    Google Scholar 

  • Edginton AN, Schmitt W, Willmann S (2006b) Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet 45(10):1013–1034

    Google Scholar 

  • Engle WA (2004) Age terminology during the perinatal period. Pediatrics 114(5):1362–1364

    Article  PubMed  Google Scholar 

  • Gardner SN (2002) Modeling multi-drug chemotherapy: tailoring treatment to individuals. J Theor Biol 214(2):181–207

    Article  CAS  PubMed  Google Scholar 

  • Ge Y, Haska CL, LaFiura K, Devidas M, Linda SB, Liu M, Thomas R, Taub JW, Matherly LH (2007) Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the children’s oncology group. Clin Cancer Res 13(2 Pt 1):451–457

    Article  CAS  PubMed  Google Scholar 

  • Ginsberg G, Hattis D, Miller R, Sonawane B (2004) Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics 113(4 Suppl):973–983

    PubMed  Google Scholar 

  • Hayton WL (2000) Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS Pharm Sci 2(1):E3

    CAS  Google Scholar 

  • Johnson TN (2005) Modelling approaches to dose estimation in children. Br J Clin Pharmacol 59(6):663–669

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Johnson TN (2008) The problems in scaling adult drug doses to children. Arch Dis Child 93(3):207–211

    Article  CAS  PubMed  Google Scholar 

  • Johnson TN, Thomson M (2008) Intestinal metabolism and transport of drugs in children: the effects of age and disease. J Pediatr Gastroenterol Nutr 47(1):3–10

    Article  CAS  PubMed  Google Scholar 

  • Johnson TN, Rostami-Hodjegan A, Tucker GT (2006) Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 45(9):931–956

    Article  CAS  PubMed  Google Scholar 

  • Johnson TN, Tucker GT, Rostami-Hodjegan A (2008) Development of CYP2D6 and CYP3A4 in the first year of life. Clin Pharmacol Ther 83(5):670–671

    Article  CAS  PubMed  Google Scholar 

  • Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003a) Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167

    Google Scholar 

  • Kearns GL, Robinson PK, Wilson JT, Wilson-Costello D, Knight GR, Ward RM, van den Anker JN (2003b) Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther 74(4):312–325

    Google Scholar 

  • Kohyama J, Iwakawa Y (1990) Developmental changes in phasic sleep parameters as reflections of the brain-stem maturation: polysomnographical examinations of infants, including premature neonates. Electroencephalogr Clin Neurophysiol 76(4):325–330

    Article  CAS  PubMed  Google Scholar 

  • Läer S, Elshoff JP, Meibohm B, Weil J, Mir TS, Zhang W, Hulpke-Wette M (2005) Development of a safe and effective pediatric dosing regimen for sotalol based on population pharmacokinetics and pharmacodynamics in children with supraventricular tachycardia. J Am Coll Cardiol 46:1322–1330

    Article  PubMed  Google Scholar 

  • Laer S, Barrett JS, Meibohm B (2009) The in silico child: using simulation to guide pediatric drug development and manage pediatric pharmacotherapy. J Clin Pharmacol 49(8):889–904

    Article  CAS  PubMed  Google Scholar 

  • Maharaj AR, Barrett JS, Edginton AN (2013) A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J 15(2):455–464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mondick JT, Gibiansky L, Gastonguay MR, Skolnik JM, Cole M, Veal GJ, Boddy AV, Adamson PC, Barrett JS (2008) Population pharmacokinetic investigation of actinomycin-D in children and young adults. J Clin Pharmacol 48(1):35–42

    Article  CAS  PubMed  Google Scholar 

  • Potts AL, Anderson BJ, Warman GR, Lerman J, Diaz SM, Vilo S (2009) Dexmedetomidine pharmacokinetics in pediatric intensive care—a pooled analysis. Paediatr Anaesth 19(11):1119–1129

    Article  PubMed  Google Scholar 

  • Revel-Vilk S, Chan AK (2003) Anticoagulation therapy in children. Semin Thromb Hemost 29(4):425–432

    Article  CAS  PubMed  Google Scholar 

  • Rodman JH (1994) Pharmacokinetic variability in the adolescent: implications of body size and organ function for dosage regimen design. J Adolesc Health 15(8):654–662

    Article  CAS  PubMed  Google Scholar 

  • Shi J, Ludden TM, Melikian AP, Gastonguay MR, Hinderling PH (2001) Population pharmacokinetics and pharmacodynamics of sotalol in pediatric patients with supraventricular or ventricular tachyarrhythmia. J Pharmacokinet Pharmacodyn 28:555–575

    Article  CAS  PubMed  Google Scholar 

  • Stevens JC, Marsh SA, Zaya MJ, Regina KJ, Divakaran K, Le M, Hines RN (2008) Developmental changes in human liver CYP2D6 expression. Drug Metab Dispos 36(8):1587–1593

    Article  CAS  PubMed  Google Scholar 

  • Strolin Benedetti M, Baltes EL (2003) Drug metabolism and disposition in children. Fundam Clin Pharmacol 17(3):281–299

    Article  CAS  PubMed  Google Scholar 

  • Tod M, Jullien V, Pons G (2008) Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet 47(4):231–243

    Article  CAS  PubMed  Google Scholar 

  • Wade KC, Wu D, Kaufman DA, Ward RM, Benjamin DK Jr, Sullivan JE, Ramey N, Jayaraman B, Hoppu K, Adamson PC, Gastonguay MR, Barrett JS (2008) Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother 52(11):4043–4049

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y, Jadhav PR, Lala M, Gobburu JV (2012) Clarification on precision criteria to derive sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol 52(10):1601–1606

    Article  CAS  PubMed  Google Scholar 

  • Ward RM, Kauffman R (2007) Future of pediatric therapeutics: reauthorization of BPCA and PREA. Clin Pharmacol Ther 81(4):477–479

    Article  CAS  PubMed  Google Scholar 

  • Yang F, Tong X, McCarver DG, Hines RN, Beard DA (2006) Population-based analysis of methadone distribution and metabolism using an age-dependent physiologically based pharmacokinetic model. J Pharmacokinet Pharmacodyn 33(4):485–518

    Article  CAS  PubMed  Google Scholar 

  • Zuppa AF, Barrett JS (2008) Pharmacokinetics and pharmacodynamics in the critically ill child. Pediatr Clin North Am 55(3):735–755, xii

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Interdisciplinary Pharmacometrics Program, Pediatric Clinical Pharmacology, Sanofi Pharmaceuticals, 55 Corporate Drive, 08807, Bridgewater, NJ, USA

    Jeffrey Barrett

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  1. Jeffrey Barrett
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Correspondence to Jeffrey Barrett .

Editor information

Editors and Affiliations

  1. University of Florida, Department of Pharmaceutics, Center for Pharmacometrics & Systems Pharmacology, Orlando, Florida, USA

    Stephan Schmidt

  2. University of Florida, College of Pharmacy, Department of Pharmaceutics, Gainesville, Florida, USA

    Hartmut Derendorf

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© 2014 American Association of Pharmaceutical Scientists

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Barrett, J. (2014). Pharmacometrics in Pediatrics. In: Schmidt, S., Derendorf, H. (eds) Applied Pharmacometrics. AAPS Advances in the Pharmaceutical Sciences Series, vol 14. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1304-6_3

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