Pediatric pharmacokinetic considerations and implications for drug dosing
Abstract
Optimizing the dosing of medicines for pediatric patients in routine clinical practice and determining the dose for clinical trials is still a challenging task. Children differ from adults in their response to drugs due to inherent differences in pharmacokinetics and/or pharmacodynamics, and responses may also vary among pediatric patients of different ages. However, the greatest disparities compared to adult pharmacokinetic profiles are observed in children below 2 years of age. The maturation of the liver and the kidneys, as well as the variation in body composition, are considered to be the main sources of pharmacokinetic variability. Hence, besides specific pharmacodynamic features, understanding age-related changes in drug absorption, distribution, and elimination is fundamental for optimizing drug efficacy and avoiding toxicity. This paper summarizes the pharmacokinetic changes throughout the childhood, along with the effect of developmental changes on drug dosage calculation. In clinical practice, age and body weight-based dosing regimens are usually used. In spite of dosing recommendations based on age and/or body weight, variabilities in pharmacokinetics and pharmacodynamic response remain, implying a need to monitor patients and optimize the dosing regimen according to physiological characteristics, disease characteristics and therapy.
References
Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clin Pharmacokinet. 2014;53(4):327-46.
Job KM, Gamalo M, Ward RM. Pediatric age groups and approach to studies. Ther Innov Regul Sci. 2019;53(5):584-589.
van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental changes in pharmacokinetics and pharmacodynamics. J Clin Pharmacol. 2018;58 Suppl 10:S10-S25.
Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303-32.
De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA. The role of population PK-PD modelling in paediatric clinical research. Eur J Clin Pharmacol. 2011;67 Suppl 1:5-16.
Barker CIS, Standing JF, Kelly LE, Hanly Faught L, Needham AC, Rieder MJ, et al. Pharmacokinetic studies in children: recommendations for practice and research. Arch Dis Child. 2018;103(7):695-702.
Baber N, Pritchard D. Dose estimation for children. Br J Clin Pharmacol. 2003;56(5):489-93.
Andrade SRA, Santos P, Andrade PHS, da Silva WB. Unlicensed and off-label prescription of drugs to children in primary health care: A systematic review. J Evid Based Med. 2020;13(4):292-300.
Matalova P, Urbanek K, Anzenbacher P. Specific features of pharmacokinetics in children. Drug Metab Rev. 2016;48(1):70-9.
Batchelor HK, Marriott JF. Paediatric pharmacokinetics: key considerations. Br J Clin Pharmacol. 2015;79(3):395-404.
Huang NN, High RH. Comparison of serum levels following the administration of oral and parenteral preparations of penicillin to infants and children of various age groups. J Pediatr. 1953;42(6):657-8.
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.
Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077-97.
de Wildt SN, Tibboel D, Leeder JS. Drug metabolism for the paediatrician. Arch Dis Child. 2014;99(12):1137-42.
Krekels EHJ, Rower JE, Constance JE, Knibbe CAJ, Sherwin CMT. Hepatic drug metabolism in pediatric patients. In: Xie W, editor. Drug Metabolism in Diseases. San Francisco (CA): Elsevier Inc.; 2017; p. 181-206.
Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver-evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997;247(2):625-34.
Levy G, Khanna NN, Soda DM, Tsuzuki O, Stern L. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics. 1975;55(6):818-25.
Marsot A. Pharmacokinetic variability in pediatrics and intensive care: toward a personalized dosing approach. J Pharm Pharm Sci. 2018;21(1):354-362.
Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011;21(3):222-37.
Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98(9):737-44.
Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52.
Mathur S, Jackson C, Urus H, Ziarko I, Goodbun M, Hsia Y, et al. A comparison of five paediatric dosing guidelines for antibiotics. Bull World Health Organ. 2020;98(6):406-412F.
Vučićević K, Miljković B, Prostran M. Pharmacokinetic considerations in drug dosing to pediatric obese patients. MD - Medical data. 2016;8(3):149-153.
O'Hara K. Paediatric pharmacokinetics and drug doses. Aust Prescr 2016;39(6):208-210.
Duffull SB, Wright DF, Winter HR. Interpreting population pharmacokinetic-pharmacodynamic analyses - a clinical viewpoint. Br J Clin Pharmacol. 2011;71(6):807-14.
Byon W, Smith MK, Chan P, Tortorici MA, Riley S, Dai H, et al. Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CPT Pharmacometrics Syst Pharmacol. 2013;2:e51.
Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacometrics Syst Pharmacol. 2012;1:e6.
Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;2:e38.
Kos MK, Miksic M, Jovanovic M, Roskar R, Grosek S, Grabnar I. Maturation of midazolam clearance in critically ill children with severe bronchiolitis: A population pharmacokinetic analysis. Eur J Pharm Sci. 2020;141:105095.
Germovsek E, Barker CI, Sharland M, Standing JF. Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol. 2017;83(4):777-790.
Germovsek E, Barker CIS, Sharland M, Standing JF. Pharmacokinetic-pharmacodynamic modeling in pediatric drug development, and the importance of standardized scaling of clearance. Clin Pharmacokinet. 2019;58(1):39-52.
Ince I, de Wildt SN, Wang C, Peeters MY, Burggraaf J, Jacqz-Aigrain E, et al. A novel maturation function for clearance of the cytochrome P450 3A substrate midazolam from preterm neonates to adults. Clin Pharmacokinet. 2013;52(7):555-65.
U.S. Food and Drug Administration [Internet]. Population Pharmacokinetics Guidance for Industry 2022. [cited 2022 April 5]. Available from: https://www.fda.gov/media/128793/download
European Medicines Agency [Internet]. Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population 2007. [cited 2022 April 5]. Available from: https://www.ema.europa.eu/en/role-pharmacokinetics-development-medicinal-products-paediatric-population
U.S. Food and Drug Administration [Internet]. Physiologically based pharmacokinetic analyses - format and content guidance for industry 2018. [cited 2022 April 5]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/physiologically-based-pharmacokinetic-analyses-format-and-content-guidance-industry
European Medicines Agency [Internet]. Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation 2018. [cited 2022 April 5]. Available from: https://www.ema.europa.eu/en/reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation
Kim TH, Shin S, Shin BS. Model-based drug development: Application of modeling and simulation in drug development. J Pharm Investig. 2018;48(4):431-441.
Jones HM, Mayawala K, Poulin P. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches. AAPS J. 2013;15(2):377-87.
Edginton AN. Knowledge-driven approaches for the guidance of first-in-children dosing. Paediatr Anaesth. 2011;21(3):206-13.
