Development of comprehensive and updated quantitative relationships between physiological parameters and age for pediatrics remains to be accomplished. Towards this goal, we have performed a thorough literature search and collected published data on organ weights and organ blood flow rates for 0–20-year-old male and female human subjects. The data were used to develop continuous relationships between physiological parameters and age, using a single form of mathematical equation. Four sets of equations (0–2 years male, 0–2 years female, 2–20 years male, 2–20 years female) for the body weight vs. age, height vs. age, and organ weight vs. age relationships and 2 sets of equations (0–20 years male, 0–20 years female) for organ flow rate vs. age relationship were developed. The variability of each physiological parameter was also estimated, and the equations allow simulation of a virtual population for a specific age, weight, and sex. We further compared the physiological parameters vs. age curves simulated using our equations to the existing databases (Simcyp Simulator and PK-Sim). The predicted physiological parameters were comparable between our study and the existing databases, validating our equation’s utility. Additionally, we described body weight-normalized organ weights and organ blood flow rates as a function of age, to provide an insight into how the contribution of each organ towards total body weight and total blood flow changes throughout ontogenesis. The physiological parameter database and equations presented here can serve as an open source to facilitate the development of pediatric physiologically based pharmacokinetic models.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Johnson TN. The problems in scaling adult drug doses to children. Arch Dis Child. 2008;93(3):207–11.
Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Neville KA, Paul IM, et al. Off-label use of drugs in children. Pediatrics. 2014;133(3):563–7.
Miyagi SJ, Long-Boyle JR. Predicting pediatric drug disposition-present and future directions of pediatric physiologically-based pharmacokinetics. Drug Metab Lett. 2015;9(2):80–7.
Mehrotra N, Bhattaram A, Earp JC, Florian J, Krudys K, Lee JE, et al. Role of quantitative clinical pharmacology in pediatric approval and labeling. Drug Metab Dispos. 2016;44(7):924–33.
Vermeulen E, van den Anker JN, Della Pasqua O, Hoppu K, van der Lee JH. How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians. J Pharm Pharmacol. 2017;69(4):439–47.
Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther. 2014;19(4):262–76.
Edginton AN. Using physiologically based pharmacokinetic modeling for mechanistic insight: cases of reverse translation. Clin Transl Sci. 2018;11(2):109–11.
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.
Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J. 2013;15(2):455–64.
Templeton IE, Jones NS, Musib L. Pediatric dose selection and utility of PBPK in determining dose. AAPS J. 2018;20(2):31.
European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation. 2016.
Flerlage JE, Metzger ML, Wu J, Panetta JC. Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma. Cancer Chemother Pharmacol. 2016;78(6):1217–23.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology-drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.
Price PS, Conolly RB, Chaisson CF, Gross EA, Young JS, Mathis ET, et al. Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol. 2003;33(5):469–503.
Haddad S, Restieri C, Krishnan K. Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health A. 2001;64(6):453–64.
Shah DK, Haddish-Berhane N, Betts A. Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. J Pharmacokinet Pharmacodyn. 2012;39(6):643–59.
Shah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39(1):67–86.
Edginton AN, Ritter L. Predicting plasma concentrations of bisphenol A in children younger than 2 years of age after typical feeding schedules, using a physiologically based toxicokinetic model. Environ Health Perspect. 2009;117(4):645–52.
Kuepfer L, Niederalt C, Wendl T, Schlender JF, Willmann S, Lippert J, et al. Applied concepts in PBPK modeling: how to build a PBPK/PD model. CPT Pharmacometrics Syst Pharmacol. 2016;5(10):516–31.
Huang SM, Rowland M. The role of physiologically based pharmacokinetic modeling in regulatory review. Clin Pharmacol Ther. 2012;91(3):542–9.
Price K, Haddad S, Krishnan K. Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children. J Toxicol Environ Health A. 2003;66(5):417–33.
Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45(10):1013–34.
Basu S, Lien YTK, Vozmediano V, Schlender JF, Eissing T, Schmidt S, et al. Physiologically based pharmacokinetic modeling of monoclonal antibodies in pediatric populations using PK-Sim. Front Pharmacol. 2020;11:868.
Pan X, Stader F, Abduljalil K, Gill KL, Johnson TN, Gardner I, et al. Development and application of a physiologically-based pharmacokinetic model to predict the pharmacokinetics of therapeutic proteins from full-term neonates to adolescents. AAPS J. 2020;22(4):76.
Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP. 2002;32(3–4):5–265.
Willmann S, Höhn K, Edginton A, Sevestre M, Solodenko J, Weiss W, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007;34(3):401–31.
Wells JCK, Fewtrell MS. Measuring body composition. Arch Dis Child. 2006;91(7):612–7.
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. CDC growth charts for the United States: methods and development. Vital Health Stat 11. 2000;2002(246):1–190.
Organization WH. WHO child growth standards: WHO press; 2006 [Available from: https://www.who.int/childgrowth/standards/Technical_report.pdf?ua=1.]
Wu PY, Wong WH, Guerra G, Miranda R, Godoy RR, Preston B, et al. Peripheral blood flow in the neonate; 1. Changes in total, skin, and muscle blood flow with gestational and postnatal age. Pediatr Res. 1980;14(12):1374–8.
Li D, Poon KA, Yu S-F, Dere R, Go M, Lau J, et al. DCDT2980S, an anti-CD22- monomethyl auristatin E antibody–drug conjugate, is a potential treatment for non-Hodgkin lymphoma. Mol Cancer Ther. 2013;12(7):1255–65.
Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, et al. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21(22):5139–50.
Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9.
Snyder WS, Cook MJ, Nasset ES, Karhausen LR, Howells GP, Tipton IH. Report of the task group on reference man. First ed: Pergamon Press; 1975.
Williams LR, Leggett RW. Reference values for resting blood flow to organs of man. Clin Phys Physiol Meas. 1989;10(3):187–217.
Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;59(6):691–704.
Linderkamp O, Versmold HT, Riegel KP, Betke K. Estimation and prediction of blood volume in infants and children. Eur J Pediatr. 1977;125(4):227–34.
Redlarski G, Palkowski A, Krawczuk M. Body surface area formulae: an alarming ambiguity. Sci Rep. 2016;6(1):27966.
Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr. 1978;93(1):62–6.
Tan CY, Statham B, Marks R, Payne PA. Skin thickness measurement by pulsed ultrasound: its reproducibility, validation and variability. Br J Dermatol. 1982;106(6):657–67.
Gallagher D, Heymsfield SB, Wang Z-M. Protein and amino acids: National Academy Press; 1999.
Poortmans JR, Boisseau N, Moraine JJ, Moreno-Reyes R, Goldman S. Estimation of total-body skeletal muscle mass in children and adolescents. Med Sci Sports Exerc. 2005;37(2):316–22.
Kim J, Shen W, Gallagher D, Jones A Jr, Wang Z, Wang J, et al. Total-body skeletal muscle mass: estimation by dual-energy X-ray absorptiometry in children and adolescents. Am J Clin Nutr. 2006;84(5):1014–20.
Webber CE, Barr RD. Age- and gender-dependent values of skeletal muscle mass in healthy children and adolescents. J Cachexia Sarcopenia Muscle. 2012;3(1):25–9.
Fujii K, Ishizaki A, Ogawa A, Asami T, Kwon H, Tanaka A, et al. Validity of using multi-frequency bioelectrical impedance analysis to measure skeletal muscle mass in preschool children. J Phys Ther Sci. 2017;29(5):863–8.
Fomon SJ, Haschke F, Ziegler EE, Nelson SE. Body composition of reference children from birth to age 10 years. Am J Clin Nutr. 1982;35(5 Suppl):1169–75.
Friis-Hansen B. The extracellular fluid volume in infants and children. Acta Paediatr. 1954;43(5):444–58.
Latka M, Wojtowicz K, Drozdz T, Dabrowska E, Kwinta P, Pietrzyk JA, et al. Relationship between water compartments, body composition assessed by bioelectrical impedance analysis and blood pressure in school children. Przegl Lek. 2016;73(1):1–5.
Butte NF, Hopkinson JM, Wong WW, Smith EO, Ellis KJ. Body composition during the first 2 years of life: an updated reference. Pediatr Res. 2000;47(5):578–85.
Cech P, T. M, Mala L, F. Z. Body composition of elite youth pentathletes and its gender differences. Sport Sci. 2013;6(2):29–35.
Bindler RC, Howry LB, Wilson BA, Shannon MT, Stang CL. Prentice hall pediatric drug guide. 1 ed: Pearson; 2005 March. 1376 p.
Friis-Hansen B. Body water compartments in children: changes during growth and related changes in body composition. Pediatrics. 1961;28:169–81.
Knittle JL, Timmers K, Ginsberg-Fellner F, Brown RE, Katz DP. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest. 1979;63(2):239–46.
Laurson KR, Eisenmann JC, Welk GJ. Body fat percentile curves for U.S. children and adolescents. Am J Prev Med. 2011;41(4 Suppl 2):S87–92.
Weber DR, Leonard MB, Zemel BS. Body composition analysis in the pediatric population. Pediatr Endocrinol Rev. 2012;10(1):130–9.
Wells JC. Toward body composition reference data for infants, children, and adolescents. Adv Nutr. 2014;5(3):320S–9S.
Toro-Ramos T, Paley C, Pi-Sunyer FX, Gallagher D. Body composition during fetal development and infancy through the age of 5 years. Eur J Clin Nutr. 2015;69(12):1279–89.
Shankle WR, Landing BH, Gregg J. Normal organ weights of infants and children: graphs of values by age, with confidence intervals. Pediatr Pathol. 1983;1(4):399–408.
Chang HY, Wu S, Meno-Tetang G, Shah DK. A translational platform PBPK model for antibody disposition in the brain. J Pharmacokinet Pharmacodyn. 2019;46(4):319–38.
Zanchetta JR, Plotkin H, Alvarez Filgueira ML. Bone mass in children: normative values for the 2–20-year-old population. Bone. 1995;16(4 Suppl):393s–9s.
Looker AC, Borrud LG, Hughes JP, Fan B, Shepherd JA, Sherman M. Total body bone area, bone mineral content, and bone mineral density for individuals aged 8 years and over: United States, 1999-2006. Vital Health Stat 11 2013(253):1–78.
Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF. Whole body bone mineral content in healthy children and adolescents. Arch Dis Child. 1997;76(1):9–15.
Specker BL, Johannsen N, Binkley T, Finn K. Total body bone mineral content and tibial cortical bone measures in preschool children. J Bone Miner Res. 2001;16(12):2298–305.
Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011;26(8):1729–39.
Gallo S, Vanstone CA, Weiler HA. Normative data for bone mass in healthy term infants from birth to 1 year of age. J Osteoporos. 2012;2012:672403.
Lifshitz F, Hecht JP, Bermudez EF, Gamba CA, Reinoso JM, Casavalle PL, et al. Body composition analysis by dual-energy X-ray absorptiometry in young preschool children. Eur J Clin Nutr. 2016;70(10):1203–9.
ICRP, 1995. Basic anatomical & physiological data for use in radiological protection–the skeleton. ICRP Publication 70. Ann. ICRP 25 (2).
Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth. 1976;40(4):329–41.
Richardson RB, Allan DS, Le Y. Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans. Exp Gerontol. 2014;55:80–91.
Pryce JW, Bamber AR, Ashworth MT, Kiho L, Malone M, Sebire NJ. Reference ranges for organ weights of infants at autopsy: results of >1,000 consecutive cases from a single centre. BMC Clin Pathol. 2014;14:18.
Geelhoed JJ, Taal HR, Steegers EA, Arends LR, Lequin M, Moll HA, et al. Kidney growth curves in healthy children from the third trimester of pregnancy until the age of two years. The Generation R Study Pediatr Nephrol. 2010;25(2):289–98.
Tahka H. The weight of the thymus in children of 0-2 years. Acta Paediatr. 1951;40(6):469–85.
Macauley M, Percival K, Thelwall PE, Hollingsworth KG, Taylor R. Altered volume, morphology and composition of the pancreas in type 2 diabetes. PLoS One. 2015;10(5):e0126825.
Kin T, Murdoch TB, Shapiro AM, Lakey JR. Estimation of pancreas weight from donor variables. Cell Transplant. 2006;15(2):181–5.
Virostko J, Hilmes M, Eitel K, Moore DJ, Powers AC. Use of the electronic medical record to assess pancreas size in type 1 diabetes. PLoS One. 2016;11(7):e0158825.
Innes JT, Carey LC. Normal pancreatic dimensions in the adult human. Am J Surg. 1994;167(2):261–3.
Abduljalil K, Jamei M, Johnson TN. Fetal physiologically based pharmacokinetic models: systems information on the growth and composition of fetal organs. Clin Pharmacokinet. 2019;58(2):235–62.
Wu C, Honarmand AR, Schnell S, Kuhn R, Schoeneman SE, Ansari SA, et al. Age-related changes of normal cerebral and cardiac blood flow in children and adults aged 7 months to 61 years. J Am Heart Assoc. 2016;5(1).
Grunert D, Schoning M, Rosendahl W. Renal blood flow and flow velocity in children and adolescents: duplex Doppler evaluation. Eur J Pediatr. 1990;149(4):287–92.
Visser MO, Leighton JO, van de Bor M, Walther FJ. Renal blood flow in neonates: quantification with color flow and pulsed Doppler US. Radiology. 1992;183(2):441–4.
Elia M, Kurpad A. What is the blood flow to resting human muscle? Clin Sci (Lond). 1993;84(5):559–63.
Wu PY, Wong WH, Hodgman JE, Levan N. Changes in blood flow in the skin and muscle with phototherapy. Pediatr Res. 1974;8(4):257–62.
Hodges GJ, Sharp L, Clements RE, Goldspink DF, George KP, Cable NT. Influence of age, sex, and aerobic capacity on forearm and skin blood flow and vascular conductance. Eur J Appl Physiol. 2010;109(6):1009–15.
Imms FJ, Kelly DH. Variations of forearm blood flow with age and sex. J Gerontol. 1966;21(3):432–4.
Picton-Warlow CG, Mayer FE. Cardiovascular responses to postural changes in the neonate. Arch Dis Child. 1970;45(241):354–9.
Kenney WL, Ho CW. Age alters regional distribution of blood flow during moderate- intensity exercise. J Appl Physiol (1985). 1995;79(4):1112–1119.
Ho CW, Beard JL, Farrell PA, Minson CT, Kenney WL. Age, fitness, and regional blood flow during exercise in the heat. J Appl Physiol (1985). 1997;82(4):1126–1135.
Pichler G, Urlesberger B, Jirak P, Zotter H, Reiterer E, Muller W, et al. Reduced forearm blood flow in children and adolescents with type 1 diabetes (measured by near-infrared spectroscopy). Diabetes Care. 2004;27(8):1942–6.
Samánek M, Goetzová J, Fiserová J, Skovránek J. Differences in muscle blood flow in upper and lower extremities of patients after correction of coarctation of the aorta. Circulation. 1976;54(3):377–81.
Carlisle KM, Halliwell M, Read AE, Wells PN. Estimation of total hepatic blood flow by duplex ultrasound. Gut. 1992;33(1):92–7.
Verscheijden LFM, Koenderink JB, de Wildt SN, Russel FGM. Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis. PLoS Comput Biol. 2019;15(6):e1007117.
de Onis M, Garza C, Victora CG, Onyango AW, Frongillo EA, Martines J. The WHO Multicentre Growth Reference Study: planning, study design, and methodology. Food Nutr Bull. 2004;25(1 Suppl):S15–26.
Joe F. Hair CMRMS. PLS-SEM: indeed a silver bullet. J Mark Theory Pract 2011;19:2:139–152.
Brinkman JE, Dorius B, Sharma S. Physiology, body fluids. [Updated 2020 May 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482447/.
Zwilling E. Growth, including reproduction and morphological development. Compiled and edited by Philip L. Altman and Dorothy S. Dittmer. Federation of American Societies for Experimental Biology, Washington, D.C., 1962. xiv +608 pp. Illus. $12.50. Science. 1963;140(3567):638–639.
Nestorov I. Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics. Toxicol Lett. 2001;120(1–3):411–20.
Watanabe KH, Bois FY. Interspecies extrapolation of physiological pharmacokinetic parameter distributions. Risk Anal. 1996;16(6):741–54.
Bois FY, Krowech G, Zeise L. Modeling human interindividual variability in metabolism and risk: the example of 4-aminobiphenyl. Risk Anal. 1995;15(2):205–13.
Brussee JM, Yu H, Krekels EHJ, Palić S, Brill MJE, Barrett JS, et al. Characterization of intestinal and hepatic CYP3A-mediated metabolism of midazolam in children using a physiological population pharmacokinetic modelling approach. Pharmaceutical research. 2018;35(9):182.
Behrman RE, Kliegman RM, Jenson HP, editors. Textbook of pediatrics. 16. Philadelphia: Saunders; 2000.
Gonzalez D, Delmore P, Bloom BT, Cotten CM, Poindexter BB, McGowan E, et al. Clindamycin pharmacokinetics and safety in preterm and term infants. Antimicrob Agents Chemother. 2016;60(5):2888–94.
Abduljalil K, Pan X, Pansari A, Jamei M, Johnson TN. A preterm physiologically based pharmacokinetic model. Part I: physiological parameters and model building. Clin Pharmacokinet. 2020;59(4):485–500.
Claassen K, Thelen K, Coboeken K, Gaub T, Lippert J, Allegaert K, et al. Development of a physiologically-based pharmacokinetic model for preterm neonates: evaluation with in vivo data. Curr Pharm Des. 2015;21(39):5688–98.
Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008;118(2):250–67.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Chang, H.P., Kim, S.J., Wu, D. et al. Age-Related Changes in Pediatric Physiology: Quantitative Analysis of Organ Weights and Blood Flows. AAPS J 23, 50 (2021). https://doi.org/10.1208/s12248-021-00581-1
- organ blood flow
- organ weight
- physiological parameters