Skip to main content

How to Estimate the Dose to Be Given for the First Time to Pediatric Patients

  • 2543 Accesses

Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS,volume 11)

Abstract

Current FDA guidance (Food and Drug Administration, Guidance for Industry: General considerations for pediatric pharmacokinetic studies for drugs and biological products. U.S. Department of Health and Human Services, Rockville, MD, November 1998) recommends administration of a fraction of an adult dose to pediatric patients based on mg/kg of bodyweight (BW) or mg/m2 of body surface area extrapolation of adult doses. However, children are not small adults, and it is recommended to use the systemic exposure [usually the area under the curve (AUC)] to guide the starting dose selection in pediatrics. Systemic exposure is typically the AUC observed at the therapeutic dose in adults. This approach implies the ability to predict the pharmacokinetics in pediatric patients. There are several techniques to predict the pharmacokinetics in children based on knowledge of the pharmacokinetics in adults. The preferred approach is physiologically based pharmacokinetic (PBPK) modeling. PBPK models account for developmental differences between adults and children of differing ages and incorporate known maturation and variability in clearance processes and distribution. However in cases when the PBPK approach is not possible, the recommendation is to use allometry. In the case of larger molecules (for example, with biological products), an mg/kg or allometric scaling approach may be appropriate, unless there is prior information that provides a more drug-specific way to calculate the starting dose. Additional information like the use of a safety factor and other approaches to estimate the starting dose in pediatrics will be described in this chapter.

Keywords

  • Body Surface Area
  • PBPK Model
  • Allometric Scaling
  • Adult Dose
  • Pediatric Dose

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4899-8011-3_5
  • Chapter length: 13 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-1-4899-8011-3
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   219.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Fig. 5.1
Fig. 5.2
Fig. 5.3
Fig. 5.4
Fig. 5.5

References

  1. ICH Topic E 11 (2001) Clinical investigation of medicinal products in the paediatric population. CPMP/ICH/2711/99 (January 2001)

    Google Scholar 

  2. Food and Drug Administration (2003) Guidance for industry: exposure-response relationships – study design, data analysis, and regulatory applications. U.S. Department of Health and Human Services, Rockville (April 2003)

    Google Scholar 

  3. Food and Drug Administration (1998) Guidance for industry: general considerations for pediatric pharmacokinetic studies for drugs and biological products. U.S. Department of Health and Human Services, Rockville (November 1998)

    Google Scholar 

  4. Kearns GL (2003) Developmental pharmacology – drug disposition, action and therapy in infants and children. NEJM 349(12):1157–1167

    CAS  PubMed  CrossRef  Google Scholar 

  5. Alcorn J, McNamara PJ (2002) Ontogeny of hepatic and renal systemic clearance pathways in infants. Part I. Clin Pharmacokinet 41(12):959–998

    CAS  PubMed  CrossRef  Google Scholar 

  6. Alcorn J, McNamara PJ (2002) Ontogeny of hepatic and renal systemic clearance pathways in infants. Part II. Clin Pharmacokinet 41(13):1077–1094

    CAS  PubMed  CrossRef  Google Scholar 

  7. Bartelink IH (2006) Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet 45(11):1077–1097

    CAS  PubMed  CrossRef  Google Scholar 

  8. Nestorov I (2003) Whole body pharmacokinetic models. Clin Pharmacokinet 42(10):883–908

    CAS  PubMed  CrossRef  Google Scholar 

  9. Parrott N, Jones H, Paquereau N, Lave T (2005) Application of full physiological models for pharmaceutical drug candidate selection and extrapolation of pharmacokinetics to man. Basic Clin Pharmacol Toxicol 96:193–199

    CAS  PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  11. Parrott N, Davies B et al (2011) Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. Clin Pharmacokinet 50(9):613–623

    CAS  PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  13. Björkman S (2004) Prediction of drug disposition in children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 59(6):691–704

    CrossRef  Google Scholar 

  14. Khalil F, Laër S (2011) Physiologically based pharmacokinetic modeling: methodology, applications, and limitations with a focus on its role in pediatric drug development. J Biomed Biotechnol 2011, 907461, PMID:21716673

    PubMed Central  PubMed  CrossRef  Google Scholar 

  15. Hsien L (2010) Identifying paediatric needs in cardiology and the prediction of sildenafil exposure in children with pulmonary arterial hypertension. Inauguraldissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf (July 2010)

    Google Scholar 

  16. Haddad S, Restieri C, Krishnan K (2001) Characterization of age-related changes in bodyweight and organ weights from birth to adolescence in humans. J Toxicol Environ Health 64(6):453–464

    CAS  CrossRef  Google Scholar 

  17. Manolis E, Pons G (2009) Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 68(4):493–501

    PubMed  CrossRef  Google Scholar 

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

    CAS  PubMed  CrossRef  Google Scholar 

  19. Läer S et al (2005) Population pharmacodynamics in children with supraventricular tachycardia. JACC 46(7):1322–1330

    PubMed  CrossRef  Google Scholar 

  20. Albers S, Meibohm B, Mir TS, Laër S (2007) Population pharmacokinetics and dose simulation of carvedilol in paediatric patients with congestive heart failure. Br J Clin Pharmacol 65(4):511–522

    PubMed  CrossRef  Google Scholar 

  21. Booth BP (2007) Population pharmacokinetic-based bosing of intravenous busulfan in pediatric patients. J Clin Pharmacol 47:101–111

    CAS  PubMed  CrossRef  Google Scholar 

  22. Kuczmarski RJ, Ogden CL, Guo SS et al (2002) 2000 CDC growth charts for the United States: Methods and development. National Center for Health Statistics. Vital Health Stat 11(246):1–190

    Google Scholar 

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

    CAS  CrossRef  Google Scholar 

  24. Anderson BJ, Meakin GH (2002) Scaling for size: some implications for paediatric anaesthesia dosing. Paed Anaesth 12:205–219

    CrossRef  Google Scholar 

  25. Crawford J, Terry M, Rourke G (1950) Simplification of drug dosage calculation by application of the surface area principle. Pediatrics 5:783–790

    CAS  PubMed  Google Scholar 

  26. Miminas DA (2007) A critical evaluation of the Lund and Browder chart. Wounds UK 3(3):58–66

    Google Scholar 

  27. Bailey BJR, Briars GL (1996) Estimating the surface area of the human body. Stat Med 15:1325–1332

    CAS  PubMed  CrossRef  Google Scholar 

  28. Anderson BJ, Eliis JF (1999) Common errors of drug administration in infants. Causes and avoidance. Paediatr Drugs 1(2):93–107

    CAS  PubMed  Google Scholar 

  29. Holford N (2010) Dosing in children. Clin Pharmacol Ther 87(3):367–370

    CAS  PubMed  CrossRef  Google Scholar 

  30. Mahmood I (2006) Prediction of drug clearance in children from adults: a comparison of several allometric methods. Br J Clin Pharmacol 61(5):545–587

    CAS  PubMed  CrossRef  Google Scholar 

  31. Ginsberg G et al (2002) Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci 66:185–200

    CAS  PubMed  CrossRef  Google Scholar 

  32. Scheuplein R, Charnley G, Dourson M (2002) Differential sensitivity of children and adults to chemical toxicity. I. Biological basis. Reg Toxicol Pharmacol 35:429–447

    CAS  CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gerard Greig .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2014 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Greig, G. (2014). How to Estimate the Dose to Be Given for the First Time to Pediatric Patients. In: Bar-Shalom, D., Rose, K. (eds) Pediatric Formulations. AAPS Advances in the Pharmaceutical Sciences Series, vol 11. Springer, New York, NY. https://doi.org/10.1007/978-1-4899-8011-3_5

Download citation