title: Risk assessment for extending the Biopharmaceutics Classification System-based biowaiver of immediate release dosage forms of fluconazole in adults to the paediatric population.
abstract: OBJECTIVE
  The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such as Cmax (maximum plasma concentration of drug) and area under the plasma concentration vs time profile curve. The aim of this work is to assess the risk of extending the biowaiver for immediate release dosage formulations of fluconazole from the adult to the paediatric population.
  
  
  RESULTS
  Fluconazole exhibits good solubility and very rapid dissolution characteristics in various pH media. The absorption of fluconazole in children is known to be complete (over 90%) and not impaired by elevated pH, which is prevalent during the early days of life. Dose numbers calculated using body surface area are less than 1. Therefore, the risk to drug absorption due to differences in gastric pH, gastric emptying, intestinal transit, membrane permeability and metabolising enzymes between adults and children is considered low.
  
  
  CONCLUSIONS
  Thus, it can be safely concluded that fluconazole meets highly soluble and highly permeable criteria in the paediatric population and can be allocated to class 1 of the Biopharmaceutics Classification System (BCS) for this population as well as in adults. Additionally, fluconazole has an excellent safety profile in children, similar to that in adults. The BCS-based biowaiver claimed in adults can be safely extended to the paediatric population provided that the requirements in excipient selection and dissolution profile comparison using BCS-based dissolution conditions as stated in the biowaiver monograph for fluconazole immediate release dosage forms in adults are fulfilled.
authors.affiliation: Department of Research and Development, AlFalah Life Sciences Pvt Ltd, Budgam, India.|Emirates Pharma, Dubai, United Arab Emirates.
authors.forename: Naseem A
authors.initials: NA
authors.lastname: Charoo
authors.affiliation: Division of Therapeutic Equivalence, Brazilian Health Surveillance Agency (ANVISA), Brasilia, Brazil.|Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cristofoletti
authors.affiliation: Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Dressman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001702:Biopharmaceutics / Q000145:classification*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002648:Child; D065546:Drug Liberation; D015725:Fluconazole / Q000493:pharmacokinetics*; D041981:Gastrointestinal Tract / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology; D018570:Risk Assessment; D012995:Solubility; D013810:Therapeutic Equivalency
chemical_list: D015725:Fluconazole
keywords: Biopharmaceutics Classification System; dissolution and permeability; fluconazole; metabolism; paediatric indications