Skip to main content

Advertisement

SpringerLink
Log in

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs

  • Research Article
  • Theme: Leveraging BCS Classification and in-silico Modeling for Product Development
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m2 adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

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

Fig. 1

Similar content being viewed by others

REFERENCES

  1. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. 2000. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf. Accessed 21 May 2013.

  2. 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. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  3. 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;10:289–99. doi:10.1208/s12248-008-9027-6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Cook JA, Davit BM, Polli JE. Impact of biopharmaceutics classification system-based biowaivers. Mol Pharm. 2010;7:1539–44. doi:10.1021/mp1001747.

    Article  CAS  PubMed  Google Scholar 

  5. Purohit VS. Biopharmaceutic planning in pediatric drug development. AAPS J. 2012;4:519–22. doi:10.1208/s12248-012-9364-3.

    Article  Google Scholar 

  6. Intra-Agency Agreement Between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the U.S. Food and Drug Administration (FDA) Oral Formulations Platform—Report 1. 2011. http://bpca.nichd.nih.gov/collaborativeefforts/initiatives/upload/Formulations_Table_for_Web_11-02-11.pdf. Accessed 21 May 2013.

  7. Hoff DS, Jensen PD. Pediatric pharmacotherapy. In: Hoff DS, Jensen PD, editors. Pharmacotherapy self-assessment program. 4th ed. Kansas City: American College of Clinical Pharmacy; 2003. p. 13.

    Google Scholar 

  8. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT, et al. 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 Central  PubMed  Google Scholar 

  9. ANZEMET® (dolasetron mesylate) Tablets. Sanofi-Aventis U.S. LLC. October 2003. http://products.sanofi.us/anzemet_tablets/anzemettab.pdf. Accessed 24 August 2013.

  10. Kokki H, Tuomilehto H, Karvinen M. Pharmacokinetics of ketoprofen following oral and intramuscular administration in young children. Eur J Clin Pharmacol. 2001;57(9):643–7.

    Article  CAS  PubMed  Google Scholar 

  11. Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50(1):27–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. ZITHROMAX® (azithromycin tablets and azithromycin for oral suspension). Pfizer Inc. February 2013. http://labeling.pfizer.com/ShowLabeling.aspx?id=511. Accessed 24 August 2013.

  13. CIPRO® (Ciprofloxacin Hydrochloride) TABLETS, CIPRO® (Ciprofloxacin) ORAL SUSPENSION. Bayer HealthCare Pharmaceuticals Inc. 2008. http://www.univgraph.com/bayer/inserts/ciprotab.pdf Accessed 21 May 2013.

  14. Benet LZ, Broccatelli F, Oprea TI. BDDCS applied to over 900 drugs. AAPS J. 2011;13:519–47.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Curatolo W. Interdisciplinary science and the design of a single-dose antibiotic therapy. Pharm Res. 2011;28(9):2059–71. doi:10.1007/s11095-011-0382-0.

    Article  CAS  PubMed  Google Scholar 

  16. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Mol Pharm. 2006;3(6):631–43.

    Article  CAS  PubMed  Google Scholar 

  17. Centers for Disease Control and Prevention. 2 to 20 years: Boys Stature-for-Age and Weight-for-Age Percentiles. 2000. http://www.cdc.gov/growthcharts/data/set1clinical/cj41c021.pdf Accessed 21 May 2013.

  18. Centers for Disease Control and Prevention. Birth to 36 months: Boys Length-for-Age and Weight-for-Age Percentiles. 2000. http://www.cdc.gov/growthcharts/data/set1clinical/cj41l017.pdf Accessed 21 May 2013.

  19. Coppes MJ, Yanofsky R, Pritchard S, Leclerc JM, Howard DR, Perrotta M, et al. Safety, tolerability, antiemetic efficacy, and pharmacokinetics of oral dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy. J Pediatr Hematol Oncol. 1999;21(4):274–83.

    Article  CAS  PubMed  Google Scholar 

  20. Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults. Antimicrob Agents Chemother. 2011;55(12):5770–9. doi:10.1128/AAC.00531-11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Nahata MC, Koranyi KI, Luke DR, Foulds G. Pharmacokinetics of azithromycin in pediatric patients with acute otitis media. Antimicrob Agents Chemother. 1995;39(8):1875–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Schaefer HG, Stass H, Wedgwood J, Hampel B, Fischer C, Kuhlmann J, et al. Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients. Antimicrob Agents Chemother. 1996;40(1):29–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Coppes MJ, Lau R, Ingram LC, Wiernikowski JT, Grant R, Howard DR, et al. Open-label comparison of the antiemetic efficacy of single intravenous doses of dolasetron mesylate in pediatric cancer patients receiving moderately to highly emetogenic chemotherapy. Med Pediatr Oncol. 1999;33(2):99–105.

    Article  CAS  PubMed  Google Scholar 

  24. KETOPROFEN® capsule. Mylan Pharmaceuticals Inc. 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=198a4140-f4c0-4478-9157-ee1d68d0bb96. Accessed 24 November 2013.

  25. Kokki H, Karvinen M, Suhonen P. Pharmacokinetics of intravenous and rectal ketoprofen in young children. Clin Pharmacokinet. 2003;42(4):373–9.

    Article  CAS  PubMed  Google Scholar 

  26. Kokki H. Ketoprofen pharmacokinetics, efficacy, and tolerability in pediatric patients. Pediatr Drugs. 2010;12(5):313–29.

    Article  Google Scholar 

  27. VFEND® (Voriconazole) Tablets, Oral Suspension. Pfizer Ireland Pharmaceutical 2011. http://labeling.pfizer.com/ShowLabeling.aspx?id=618. Accessed 24 November 2013.

  28. Jacobs RF, Maples HD, Aranda JV, Espinoza GM, Knirsch C, Chandra R, et al. Pharmacokinetics of intravenously administered azithromycin in pediatric patients. Pediatr Infect Dis J. 2005;24(1):34–9.

    Article  PubMed  Google Scholar 

  29. Pelotas H. Single-dose and steady-state pharmacokinetics of a new oral suspension of ciprofloxacin in, children. Pediatrics. 1998;101(4):658.

    Article  Google Scholar 

  30. Baines D. Postoperative nausea and vomiting in children. Paediatr Anaesth. 1996;6:7–14.

    Article  CAS  PubMed  Google Scholar 

  31. Sung Y. Risks and benefits of drugs used in the management of PONV. Drug Saf. 1996;14:181–97.

    Article  CAS  PubMed  Google Scholar 

  32. Olutoye O, Jantzen EC, Alexis R, Rajchert D, Schreiner MS, Watcha MF. A comparison of the costs and efficacy of ondansetron and dolasetron in the prophylaxis of postoperative vomiting in pediatric patients undergoing ambulatory surgery. Anesth Analg. 2003;97(2):390–6.

    Article  CAS  PubMed  Google Scholar 

  33. Kokki H, Karvinen M, Jekunen A. Diffusion of ketoprofen into the cerebrospinal fluid of young children. Paediatr Anaesth. 2002;12(4):313–6.

    Article  PubMed  Google Scholar 

  34. Lexi-Comp OnlineTM. Pediatric & neonatal lexi-drugs OnlineTM. Hudson: Lexi-Comp; 2013.

    Google Scholar 

  35. Knipping S, Holzhausen H, Riederer A, Bloching M. Cystic fibrosis: ultrastructural changes of nasal mucosa. Eur Arch Otorhinolaryngol. 2007;264(12):1413–8.

    Article  PubMed  Google Scholar 

  36. Polli JE, Yu LX, Cook JA, Amidon GL, Borchardt RT, Burnside BA, et al. Summary workshop report: biopharmaceutics classification system—implementation challenges and extension opportunities. J Pharm Sci. 2004;93:1375–81.

    Article  CAS  PubMed  Google Scholar 

  37. Christensson B, Nilsson-Ehle I, Ljungberg B, Linblad A, Malmborg AS, Hjelte L, et al. Increased oral bioavailability of ciprofloxacin in cystic fibrosis patients. Antimicrob Agents Chemother. 1992;36:2512–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. European Medicines Agency. Revised provisional priority list for studies into off-patent paediatric medicinal products. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500143970&mid=WC0b01ac058009a3dc. Accessed 29 April 2013.

  39. Lindell-Osuagwu L, Korhonen MJ, Saano S, Helin-Tanninen M, Naaranlahti T, Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther. 2009;34(3):277–87. Review.

    Article  CAS  PubMed  Google Scholar 

  40. Abernethy DR, Burckart GJ. Pediatric dose selection. Clin Pharmacol Ther. 2010;87:270–1.

    Article  CAS  PubMed  Google Scholar 

  41. Mahmood I. Interspecies pharmacokinetic scaling. Rockville: Pine House; 2005.

    Google Scholar 

  42. Yazdanian M, Briggs K, Jankovsky C, Hawi A. The "high solubility" definition of the current FDA guidance on biopharmaceutical classification system may be too strict for acidic drugs. Pharm Res. 2004;21(2):293–9.

    Article  CAS  PubMed  Google Scholar 

  43. Polli JE, Ginski MJ. Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm Res. 1998;15:47–52.

    Article  CAS  PubMed  Google Scholar 

  44. Lentz KA, Hayashi J, Lucisano LJ, Polli JE. Development of a more rapid, reduced serum culture system for Caco-2 monolayers and application to biopharmaceutics classification system. Int J Pharm. 2000;200(1):41–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Maryland School of Pharmacy, Baltimore, Maryland, 21201, USA

    Shivani V. Gandhi & James E. Polli

  2. Food and Drug Administration, Silver Spring, Maryland, 20993, USA

    William Rodriguez & Mansoor Khan

Authors
  1. Shivani V. Gandhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mansoor Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James E. Polli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James E. Polli.

Additional information

Guest Editors: Divyakant Desai, John Crison, and Peter Timmins

The views expressed are that of the authors and do not represent the policy of the Agency at this time.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gandhi, S.V., Rodriguez, W., Khan, M. et al. Considerations for a Pediatric Biopharmaceutics Classification System (BCS): Application to Five Drugs. AAPS PharmSciTech 15, 601–611 (2014). https://doi.org/10.1208/s12249-014-0084-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-014-0084-0

KEY WORDS

Search

Navigation