Abstract
The advances in developmental pharmacokinetics during the past decade reside with an enhanced understanding of the influence of growth and development on drug absorption, distribution, metabolism, and excretion (ADME). However, significant information gaps remain with respect to our ability to characterize the impact of ontogeny on the activity of important drug metabolizing enzymes, transporters, and other targets. The ultimate goal of rational drug therapy in neonates, infants, children, and adolescents resides with the ability to individualize it based on known developmental differences in drug disposition and action. The clinical challenge in achieving this is accounting for the variability in all of the contravening factors that influence pharmacokinetics and pharmacodynamics (e.g., genetic variants of ADME genes, different disease phenotypes, disease progression, and concomitant treatment). Application of novel technologies in the fields of pharmacometrics (e.g., in silico simulation of exposure–response relationships; disease progression modeling), pharmacogenomics and biomarker development (e.g., creation of pharmacodynamic surrogate endpoints suitable for pediatric use) are increasingly making integrated approaches for developmentally appropriate dose regimen selection possible.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alcorn J, McNamara PJ (2002) Ontogeny of hepatic and renal systemic clearance pathways in infants: part I. Clin Pharmacokinet 41:959–998
Allegaert K, Anderson BJ, Verbesselt R, Debeer A, de Hoon J, Devlieger H et al (2005) Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 activity. Br J Anaesth 95:231–239
Allegaert K, van Schaik RH, Vermeersch S, Verbesselt R, Cossey V, Vanhole C et al (2008) Postmenstrual age and CYP2D6 polymorphisms determine tramadol O-demethylation in critically ill neonates and infants. Pediatr Res 63:674–679
Allegaert K, Rochette A, Veyckemans F (2011) Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth 21(3):266–273
Anderson BJ, Holford NH (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332
Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NH (2002) Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anaesthesiology 96:1336–1345
Aranda JV, Collinge JM, Zinman R, Watters G (1979) Maturation of caffeine elimination in infancy. Arch Dis Child 54:946–949
Armstrong RW, Eichner ER, Klein DE, Barthel WF, Bennett JV, Jonsson V et al (1969) Pentachlorophenol poisoning in a nursery for newborn infants. II. Epidemiologic and toxicologic studies. J Pediatr 75:317–325
Bajpai M, Roskos LK, Shen DD, Levy RH (1996) Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 24:1401–1403
Balistreri W, Zimmer L, Suchy FJ, Bove KE (1984) Bile salt sulfotransferase: alterations during maturation and non-inducibility during substrate ingestion. J Lipid Res 25:228–235
Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN (2006) Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet 45:1077–1097
Blake MJ, Castro L, Leeder JS, Kearns GL (2005) Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonatal Med 10:123–128
Blake MJ, Abdel-Rahman SM, Pearce RE, Leeder JS, Kearns GL (2006) Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res 60:717–723
Blake MJ, Gaedigk A, Pearce RE, Bomgaars LR, Christensen ML, Stowe C et al (2007) Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther 81:510–516
Brandolese R, Scordo MG, Spina E, Gusella M, Padrini R (2001) Severe phenytoin intoxication in a subject homozygous for CYP2C9*3. Clin Pharmacol Ther 70:391–394
Brown CM, Reisfeld B, Mayeno AN (2008) Cytochromes P450: a structure-based summary of biotransformations using representative substrates. Drug Metab Rev 40:169–184
Capparelli EV, Lane JR, Romanowski GL, McFeely EJ, Murray W, Sousa P et al (2001) The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol 41:927–934
Card SE, Tompkins SF, Brien JF (1989) Ontogeny of the activity of alcohol dehydrogenase and aldehyde dehydrogenases in the liver and placenta of the guinea pig. Biochem Pharmacol 38:2535–2541
Caro AA, Cederbaum AI (2004) Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 44:27–42
Chen N, Aleksa K, Woodland C, Rieder M, Koren GL (2006) Ontogeny of drug elimination by the human kidney. Pediatr Nephrol 21:160–168
De Hoog M, Mouton JW, Schoemaker RC, Verduin CM, van den Anker JN (2002) Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring. Clin Pharmacol Ther 71:349–358
De Hoog M, Mouton JW, van den Anker JN (2005) New dosing strategies for antibacterial agents in the neonate. Semin Fetal Neonatal Med 10:185–194
De Wildt SN, Kearns GL, Leeder JS, van den Anker JN (1999) Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 36:439–452
De Wildt SN, Kearns GL, Hop WC, Murry DJ, Abdel-Rahman SM, van den Anker JN (2001) Pharmacokinetics and metabolism of intravenous midazolam in preterm infants. Clin Pharmacol Ther 70:525–531
Edginton AN, Schmitt W, Voith B, Willmann S (2006) A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet 45:683–704
Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA (2000) Caffeine citrate for the treatment of apnea of prematurity: a double-blind, placebo-controlled study. Pharmacotherapy 20:644–652
Espie P, Tytgat D, Sargentini-Maier ML, Poggesi I, Watelet JB (2009) Physiologically based pharmacokinetics (PBPK). Drug Metab Rev 41:391–407
Evans NJ, Rutter N, Hadgraft J, Parr G (1985) Percutaneous administration of theophylline in the preterm infant. J Pediatr 107:307–311
Evans WE, Relling MV, Petros WP, Meyer WH, Mirro J Jr, Crom WR (1989) Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children. Clin Pharmacol Ther 45:568–573
Feinblatt BI, Aceto T, Beckhorn G, Bruck E (1966) Percutaneous absorption of hydrocortisone in children. Am J Dis Child 112:218–224
Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 18:981–985
Friis-Hansen B (1983) Water distribution in the foetus and newborn infant. Acta Paediatr Scand 305:7–11
Gaedigk A, Simon D, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS (2008) The CYP2D6 activity score: translating genotype information into a quantitative measure of phenotype. Clin Pharmacol Ther 83:234–242
Ginsberg G, Hattis D, Miller M, Sonawane B (2004) Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics 113:973–983
Hanioka N, Tanaka-Kagawa T, Miyata Y, Matsushima E, Makino Y, Ohno A et al (2003) Functional characterization of three human cytochrome P450 2E1 variants with amino acid substitutions. Xenobiotica 33:575–586
Hayton WL (2002) Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS PharmSci 2:e3
Hines RN (2008) The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther 118:250–267
Hines RN, McCarver DG (2002) The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther 300:355–360
Holford N (2010) Dosing in children. Clin Pharmacol Ther 87:367–370
James LP, Marotti T, Stowe C, Farrar HC, Taylor B, Kearns GL (1998) Pharmacokinetics and pharmacodynamics of famotidine in infants. J Clin Pharmacol 38:1089–1095
Jimenez-Lopez JM, Cederbaum AI (2005) CYP2E1-dependent oxidative stress and toxicity: role in ethanol-induced liver injury. Expert Opin Drug Metab Toxicol 1:671–685
Johnson TN, Rostami-Hodjegan A (2011) 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 21(3):291–301
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 45:931–956
Johnson TN, Tucker GT, Rostami-Hodjegan A (2008) Development of CYP2D6 and CYP3A4 in the first year of life. Clin Pharmacol Ther 83:670–671
Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG (2003) Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther 307:402–407
Jung F, Richardson TH, Raucy JL, Johnson EF (1997) Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos 25:133–139
Kearns GL (2000) Impact of developmental pharmacology on pediatric study design: overcoming the challenges. J Allergy Clin Immunol 106:S128–S139
Kearns GL, Winter HS (2003) Proton pump inhibitors in pediatrics: relevant pharmacokinetics and pharmacodynamics. J Pediatr Gastroenterol Nutr 37(Suppl I)):S52–S59
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 349:1157–1167
Kearns GL, Robinson PK, Wilson JT, Wilson-Costello D, Knight GR, Ward RM et al (2003b) Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny. Clin Pharmacol Ther 4:312–325
Kearns GL, Jungbluth GL, Abdel-Rahman SM, Hopkins NK, Welshman IR, Grzebyk RP et al (2003c) Impact of ontogeny on linezolid disposition in neonates and infants. Clin Pharmacol Ther 74:413–422
Kearns GL, Anderson T, James LP, Gaedigk A, Kraynak RA, Abdel-Rahman SM et al (2003d) Omeprazole disposition in children following single dose administration. J Clin Pharmacol 43:840–848
Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ et al (1994) Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 47:1969–1979
Kinirons MT, O’Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ et al (1999) Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 66:224–231
Klotz U (2007) The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetics and therapeutic implications. Clin Pharmacokinet 46:271–279
Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder JS (2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 368:704
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG et al (2004) Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther 308:965–974
Kraus DM, Fischer JH, Reitz SJ, Kecskes SA, Yeh TF, McCulloch KM et al (1993) Alterations in theophylline metabolism during the first year of life. Clin Pharmacol Ther 54:351–359
Krekels EH, van den Anker JN, Baiardi P, Cella M, Cheng KY, Gibb DM et al (2007) Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations. Expert Opin Pharmacother 8:1787–1799
Lambert GH, Schoeller DA, Kotake AN, Flores C, Hay D (1986) The effect of age, gender, and sexual maturation on the caffeine breath test. Dev Pharmacol Ther 9:375–388
Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics 12:251–263
Leeder JS (2003) Developmental and pediatric pharmacogenomics. Pharmacogenomics 4:331–341
Leeder JS, Kearns GL, Spielberg SP, van den Anker JN (2010) Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol 50(12):1377–1387
Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH (1977) Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child 52:302–309
McCarver DG, Hines RN (2002) The ontogeny of human drug metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. J Pharmacol Exp Ther 300:361–366
Milavetz G, Vaughan LM, Weinberger MM, Hendeles L (1986) Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma. J Pediatr 109:351–354
Nachman RL, Esterly NB (1980) Increased skin permeability in preterm infants. J Pediatr 96:99–103
Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ et al (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42
Niemi M, Pasanen MK, Neuvonen PJ (2011) Organic anion transporting polypeptide1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63(1):157–181
Nies AT, Schwab M, Keppler D (2008) Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol 4:545–568
Payne K, Mattheyse FJ, Liedenberg D, Dawes T (1989) The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol 37:267–272
Pynnönen S, Sillanpäa M, Frey H, Iisalo E (1977) Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. Eur J Clin Pharmacol 11:129–133
Radde IC, McKercher HG (1985) Transport through membranes and development of membrane transport. In: MacLeod SM, Radde IC (eds) Textbook of pediatric clinical pharmacology. PSG, Littleton, MA, pp 1–16
Rane A, Bertilsson L, Palmer L (1975) Disposition of placentally transferred carbamazepine (Tegretol) in the newborn. Eur J Clin Pharmacol 8:283–284
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M et al (2009) Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 24:67–76
Ritschel WA, Kearns GL (eds) (2009) Handbook of basic pharmacokinetics, 7th edn. American Pharmacists Association, Washington, DC, pp 274–276
Riva R, Contin M, Albani F, Perucca E, Procaccianti G, Baruzzi A (1985) Free concentration of carbamazepine and carbamazepine-10,11-epoxide in children and adults. Influence of age and phenobarbitone co-medication. Clin Pharmacokinet 10:524–531
Roka A, Melinda KT, Vasarhelyi B, Machay T, Azzopardi D, Szabo M (2008) Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics 121:e844–e849
Russo R, Capasso M, Paolucci P, Iolascon A, TEDDY European Network of Excellence (2010) Pediatric pharmacogenetic and pharmacogenomic studies: the current state and future perspectives. Eur J Clin Pharmacol ePub 2011;67 suppl 1:17–27 Epub 2010 Nov 11
Schwab M, Eichelbaum M, Fromm MF (2003) Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol 43:285–307
Stevens JC, Hines RN, Gu C, Koukouritaki SB, Manro JR, Tandler PJ et al (2003) Developmental expression of the major human hepatic CYP3A enzymes. J Pharmacol Exp Ther 307:573–582
Stevens JC, Marsh SA, Zaya MJ, Regina KJ, Divakaran K, Le M et al (2008) Developmental changes in human liver CYP2D6 expression. Drug Metab Dispos 36:1587–1593
Strolin Benedetti M, Baltes EL (2003) Drug metabolism and disposition in children. Fundam Clin Pharmacol 17:281–299
Suzuki Y, Mimaki T, Cox S, Koepke J, Hayes J, Walson PD (1994) Phenytoin age-dose-concentration relationship in children. Ther Drug Monitor 16(2):145–150
Tateishi T, Asoh M, Yamaguchi A, Yoda T, Okano YJ, Koitabashi Y (1999) Developmental changes in urinary elimination of theophylline and its metabolites in pediatric patients. Pediatr Res 45:66–70
Treluyer JM, Jacqz-Aigrain E, Alvarez F, Cresteil T (1991) Expression of CYP2D6 in developing human liver. Eur J Biochem 202:583–588
Van den Anker JN, Rakhmanina NY (2006) Pharmacological research in pediatrics: from neonates to adolescents. Adv Drug Deliv Rev 58:4–14
Van den Anker JN, Hop W, de Groot R, van der Heijden AJ, Broerse HM, Lindemans J et al (1994) Effects of prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate in the preterm infant. Pediatr Res 36:578–581
Van den Anker JN, Schoemaker R, Hop W, van der Heijden BJ, Weber A, Sauer PJ et al (1995a) Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age. Clin Pharmacol Ther 58:650–659
Van den Anker JN, Van der Heijden AJ, Hop WCJ, Schoemaker RC, Broerse HM, Neijens HJ et al (1995b) The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn. Pediatr Res 38:808–811
Van den Anker JN, de Groot R, Broerse HM, Sauer PJ, van der Heijden BJ, Neijens HJ et al (1995c) Assessment of glomerular filtration rate in preterm infants by serum creatinine: comparison with inulin clearance. Pediatrics 96:1156–1158
Van den Anker JN, Hop WCJ, Schoemaker RC, Van der Heijden AJ, Neijens HJ, De Groot R (1995d) Ceftazidime pharmacokinetics in preterm infants: effects of postnatal age and postnatal exposure to indomethacin. Br J Clin Pharmacol 40:439–443
Van Overmeire B, Touw D, Schepens PJC, Kearns GL, van den Anker JN (2001) Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther 70:336–343
Willmann S, Edgington AN, Coboeken K, Ahr G, Lippert J (2009) Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modelling study. Clin Pharmacol Ther 86:634–643
Zanger UM, Fischer J, Raimundo S, Stuven T, Evert BO, Schwab M, Eichelbaum M (2001) Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 11:573–585
Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics and biochemistry. Naunyn-Schmiedebergs Arch Pharmacol 369:23–37
Zanger UM, Turpeinen M, Klein K, Schwab M (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392:1093–1108
Acknowledgements
Johannes van den Anker is supported in part by FP7 grants TINN (223614), TINN2 (260908), and NEUROSIS (223060), and Matthias Schwab is supported in part by the FP7 grant NEUROSIS (223060).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
van den Anker, J.N., Schwab, M., Kearns, G.L. (2011). Developmental Pharmacokinetics. In: Seyberth, H., Rane, A., Schwab, M. (eds) Pediatric Clinical Pharmacology. Handbook of Experimental Pharmacology, vol 205. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-20195-0_2
Download citation
DOI: https://doi.org/10.1007/978-3-642-20195-0_2
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-20194-3
Online ISBN: 978-3-642-20195-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)