Skip to main content
SpringerLink
Log in

Pediatric Biopharmaceutical Classification System: Using Age-Appropriate Initial Gastric Volume

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Development of optimized pediatric formulations for oral administration can be challenging, time consuming, and financially intensive process. Since its inception, the biopharmaceutical classification system (BCS) has facilitated the development of oral drug formulations destined for adults. At least theoretically, the BCS principles are applied also to pediatrics. A comprehensive age-appropriate BCS has not been fully developed. The objective of this work was to provisionally classify oral drugs listed on the latest World Health Organization’s Essential Medicines List for Children into an age-appropriate BCS. A total of 38 orally administered drugs were included in this classification. Dose numbers were calculated using age-appropriate initial gastric volume for neonates, 6-month-old infants, and children aging 1 year through adulthood. Using age-appropriate initial gastric volume and British National Formulary age-specific dosing recommendations in the calculation of dose numbers, the solubility classes shifted from low to high in pediatric subpopulations of 12 years and older for amoxicillin, 5 years, 12 years and older for cephalexin, 9 years and older for chloramphenicol, 3–4 years, 9–11 and 15 years and older for diazepam, 18 years and older (adult) for doxycycline and erythromycin, 8 years and older for phenobarbital, 10 years and older for prednisolone, and 15 years and older for trimethoprim. Pediatric biopharmaceutics are not fully understood where several knowledge gaps have been recently emphasized. The current biowaiver criteria are not suitable for safe application in all pediatric populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Batchelor HK, Fotaki N, Klein S. Paediatric oral biopharmaceutics: key considerations and current challenges. Adv Drug Deliv Rev. 2014;73:102–26. doi:10.1016/j.addr.2013.10.006.

    Article  CAS  PubMed  Google Scholar 

  2. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT. Summary of the National Institute of Child Health and Human Development-best pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group. Clin Ther. 2012;34(11):S11–24. doi:10.1016/j.clinthera.2012.09.014.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rose K. Challenges in pediatric drug development: a pharmaceutical industry perspective. Paediatr Drugs. 2009;11(1):57–9.

    Article  PubMed  Google Scholar 

  4. Zajicek A. The National Institutes of Health and the Best Pharmaceuticals for Children Act. Paediatr Drugs. 2009;11(1):45–7.

    Article  PubMed  Google Scholar 

  5. Shirkey H. Therapeutic orphans. J Pediatr. 1968;72(1):119–20.

    Article  CAS  PubMed  Google Scholar 

  6. Purohit VS. Biopharmaceutic planning in pediatric drug development. AAPS J. 2012;14(3):519–22. doi:10.1208/s12248-012-9364-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Batchelor HK, Kendall R, Desset-Brethes S, Alex R, Ernest TB. Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients. Eur J Pharm Biopharm. 2013;85(3 Pt B):833–42. doi:10.1016/j.ejpb.2013.04.015.

    Article  CAS  PubMed  Google Scholar 

  8. Gandhi SV, Rodriguez W, Khan M, Polli JE. Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs. AAPS PharmSciTech. 2014;15(3):601–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Batchelor H. Paediatric biopharmaceutics classification system: current status and future decisions. Int J Pharm. 2014;469(2):251–3. doi:10.1016/j.ijpharm.2014.02.046.

    Article  CAS  PubMed  Google Scholar 

  10. Guidance for industry: exposure-response relationships–study design, data analysis, and regulatory applications. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), April 2003.

  11. ICH Harmonised Tripartite Guideline. ICH Topic E11. Clinical Investigation of Medicinal Products in the Paediatric Population. CPMP/ICH/2711/992001. 2000.

  12. Rose K, Stötter H. ICH E 11: clinical investigation of medicinal products in the paediatric population. The International Guidance on Clinical Drug Development in Children. In: Rose K, van den Anker JN, editors. Guide to Paediatric Clinical Research. Basel: Karger; 2007. p. 33–37. doi:10.1159/000097774.

  13. Zur M, Hanson AS, Dahan A. The complexity of intestinal permeability: Assigning the correct BCS classification through careful data interpretation. Eur J Pharm Sci. 2014;61:11–7. doi:10.1016/j.ejps.2013.11.007.

    Article  CAS  PubMed  Google Scholar 

  14. Shah VP, Amidon GL, Lennernas H, Shah VP, Crison JR. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12, 413–420, 1995—Backstory of BCS. AAPS J. 2014;16(5):894–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  16. Cook J, Addicks W, Wu YH. Application of the biopharmaceutical classification system in clinical drug development—an industrial view. AAPS J. 2008;10(2):306–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guideline on the investigation of bioequivalence. Committee for Medicinal Products for Human Use, European Medicines Agency, 2010.

  18. Draft Guidance. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2015.

  19. Polli JE. In vitro studies are sometimes better than conventional human pharmacokinetic in vivo studies in assessing bioequivalence of immediate-release solid oral dosage forms. AAPS J. 2008;10(2):289–99. doi:10.1208/s12248-008-9027-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2000.

  21. Dahan A, Wolk O, Kim YH, Ramachandran C, Crippen GM, Takagi T, et al. Purely in silico BCS classification: Science based quality standards for the world’s drugs. Mol Pharm. 2013;10(11):4378–90.

    Article  CAS  PubMed  Google Scholar 

  22. Wolk O, Agbaria R, Dahan A. Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development. Drug Des Devel Ther. 2014;8:1563.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm. 2004;1(1):85–96.

    Article  CAS  PubMed  Google Scholar 

  24. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004;58(2):265–78.

    Article  PubMed  Google Scholar 

  25. Shawahna R, Rahman N. Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medicines of Pakistan. Daru. 2011;19(2):83–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Charoo NA, Cristofoletti R, Dressman JB. Risk assessment for extending the Biopharmaceutics Classification System-based biowaiver of immediate release dosage forms of fluconazole in adults to the paediatric population. J Pharm Pharmacol. 2015;67(8):1156–69. doi:10.1111/jphp.12411.

    Article  CAS  PubMed  Google Scholar 

  27. DrugBank. Open Data Drug and Drug Target database. Version 4.1 ed2014.

  28. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. World Health Organization, Technical Report Series; 2006.

  29. Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/AIDS. Pediatrics. 2007;119(4):e893–9. doi:10.1542/peds.2006-1488.

    Article  PubMed  Google Scholar 

  30. Nunn T, Williams J. Formulation of medicines for children. Br J Clin Pharmacol. 2005;59(6):674–6. doi:10.1111/j.1365-2125.2005.02410.x.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yeung VW, Wong IC. When do children convert from liquid antiretroviral to solid formulations? Pharm World Sci. 2005;27(5):399–402. doi:10.1007/s11096-005-7911-z.

    Article  PubMed  Google Scholar 

  32. 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. doi:10.2165/00003088-200645110-00003.

    Article  CAS  PubMed  Google Scholar 

  33. Meakin G, Dingwall A, Addison G. Effects of fasting and oral premedication on the pH and volume of gastric aspirate in children. Br J Anaesth. 1987;59(6):678–82.

    Article  CAS  PubMed  Google Scholar 

  34. Schwartz DA, Connelly NR, Theroux CA, Gibson CS, Ostrom DN, Dunn SM, et al. Gastric contents in children presenting for upper endoscopy. Anesth Analg. 1998;87(4):757–60.

    CAS  PubMed  Google Scholar 

  35. Crawford M, Lerman J, Christensen S, Farrow-Gillespie A. Effects of duration of fasting on gastric fluid pH and volume in healthy children. Anesth Analg. 1990;71(4):400–3.

    Article  CAS  PubMed  Google Scholar 

  36. Goetze O, Treier R, Fox M, Steingoetter A, Fried M, Boesiger P, et al. The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging. Neurogastroenterol Motil. 2009;21(7):725–e42. doi:10.1111/j.1365-2982.2009.01293.x.

  37. Stature-for-age and Weight-for-age percentiles. 2 to 20 years: Boys. Centers for Disease Control and Prevention (CDC); 2000.

  38. BNF for Children (BNFC) 2014-2015: Royal Pharmaceutical Society of Great Britain, British Medical Association, Pharmaceutical Press; 2014.

  39. Yalkowsky SH, He Y, Jain P. Handbook of aqueous solubility data. Boca Raton: CRC press; 2010.

    Book  Google Scholar 

  40. Howard P, Meylan W. Physical/chemical property database (PHYSPROP). North Syracuse NY: Syracuse Research Corporation, Environmental Science Center; 1999.

    Google Scholar 

  41. Oh DM, Curl RL, Amidon GL. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res. 1993;10(2):264–70.

    Article  CAS  PubMed  Google Scholar 

  42. Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J. 2009;11(4):740–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Maharaj AR, Edginton AN, Fotaki N. Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility. Pharm Res. 2016;33(1):52–71. doi:10.1007/s11095-015-1762-7.

    Article  CAS  PubMed  Google Scholar 

  44. Bellanti F, Della Pasqua O. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol. 2011;67 Suppl 1:75–86. doi:10.1007/s00228-010-0974-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Laer S, Barrett JS, Meibohm B. The in silico child: using simulation to guide pediatric drug development and manage pediatric pharmacotherapy. J Clin Pharmacol. 2009;49(8):889–904. doi:10.1177/0091270009337513.

    Article  CAS  PubMed  Google Scholar 

  46. Reflection paper: formulations of choice for the paediatric population. Committee for Medicinal Products for Human Use, European Medicines Agency; EMEA/CHMP/PEG/194810/2005; July 2006.

  47. Watts G. WHO launches campaign to make drugs safer for children. BMJ. 2007;335(7632), 1227. doi:10.1136/bmj.39423.581042.DB.

  48. Milne CP, Bruss JB. The economics of pediatric formulation development for off-patent drugs. Clin Ther. 2008;30(11):2133–45. doi:10.1016/j.clinthera.2008.11.019.

    Article  PubMed  Google Scholar 

  49. Breitkreutz J, Boos J. Drug delivery and formulations. In: Seyberth H, Rane A, Schwab M. Pediatric Clinical Pharmacology. Marburg: Springer; 2011. p. 91–107.

  50. Nahirya-Ntege P, Cook A, Vhembo T, Opilo W, Namuddu R, Katuramu R, et al. Young HIV-infected children and their adult caregivers prefer tablets to syrup antiretroviral medications in Africa. PLoS One. 2012;7(5), e36186. doi:10.1371/journal.pone.0036186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Khan MA, Rodriguez W. Time for a focus on pediatric friendly formulations. 2011.http://www.healio.com/pediatrics/news/print/infectious-diseases-in-children/%7B86dc3c32-9c78-43c2-10.1208/s12248-016-9885-2be51-620c2a638589%7D/time-to-focus-on-pediatric-friendly-formulations. Accessed 02 Jan 2016.

  52. Pediatric Research Equity Act. 2007. US Department of Health and Human Services, Food and Drug Administration; 2007.

  53. Best Pharmaceuticals for Children Act. Food and Drug Administration Amendments Act, US Department of Health and Human Services, Food and Drug Administration, 2007.

  54. European Parliament and Council Regulation No. 1901/2006 on Medicinal products for paediatric use. European Medicines Agency; 2006.

  55. Pediatric Formulations Initiative Workshop. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the U.S. Food and Drug Administration (FDA), Meeting Minutes for Pediatric Formulation Initiative Workshop. Best Pharmaceuticals for Children Act. Pediatric Formulations Initiative Workshop. Best Pharmaceuticals for Children Act. Pediatric Formulations Initiative Workshop; 2011.

  56. Strolin Benedetti M, Baltes E. Drug metabolism and disposition in children. Fundam Clin Pharmacol. 2003;17(3):281–99.

    Article  CAS  PubMed  Google Scholar 

  57. Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M, Ramos JT. Factors and mechanisms for pharmacokinetic differences between pediatric population and adults. Pharmaceutics. 2011;3(1):53–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Brouwer KL, Aleksunes LM, Brandys B, Giacoia GP, Knipp G, Lukacova V, et al. Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group. Clin Pharmacol Ther. 2015;98(3):266–87. doi:10.1002/cpt.176.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Pharmacology and Toxicology, Faculty of Medicine & Health Sciences, An-Najah National University, New Campus, Building: 19, Office: 1340, P.O. Box 7, Nablus, Palestine

    Ramzi Shawahna

  2. An-Najah BioSciences Unit, Center for Poison Control, Chemical and Biological Analyses, An-Najah National University, Nablus, Palestine

    Ramzi Shawahna

Authors
  1. Ramzi Shawahna
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramzi Shawahna.

Ethics declarations

Conflict of Interests

None

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 213 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shawahna, R. Pediatric Biopharmaceutical Classification System: Using Age-Appropriate Initial Gastric Volume. AAPS J 18, 728–736 (2016). https://doi.org/10.1208/s12248-016-9885-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-016-9885-2

KEY WORDS

Search

Navigation