title: Development of in vivo bioequivalence methodology for dermatologic corticosteroids based on pharmacodynamic modeling.
abstract: BACKGROUND
  Dermatologic corticosteroid products produce skin blanching that is related to clinical potency and dose. (For application of the vasoconstrictor assay to bioavailability and bioequivalence assessment, dose is defined in terms of duration of treatment exposure [dose duration], so the terms dose and dose duration have been used interchangeably). The vasoconstrictor assay is the method of choice to assess dermatologic corticosteroid products bioequivalence if dose-response is validated. This article examines dose-response validation to meet objectives of US Food and Drug Administration (FDA) bioequivalence guidance for dermatologic corticosteroid products.
  
  
  METHODS
  An exploratory dose-response study was conducted to determine applicability of the empirical maximum effect (Emax) model to the individual subject and population dose-response relationships of six dermatologic corticosteroid product creams that varied from the most to the least potent classes. Products were applied to the skin of 10 healthy subjects in each of two dosing periods for dose durations of 0.5, 1, 2, and 6 hours. Skin blanching was measured by reflectance colorimeter through 24 hours after application. Area under the effect curve (AUEC) was determined for each dose duration. An Emax model was fitted to the AUEC versus dose duration data. A similar analysis was conducted for a bioequivalence study on two formulations of a dermatologic corticosteroid product in 40 healthy subjects.
  
  
  RESULTS
  In the exploratory study, the number of individual subject data sets for which the Emax model provided an acceptable fit generally increased with the potency of the dermatologic corticosteroid product. On the basis of population modeling, dose-response data of all products, except the lowest potency cream, were adequately described by the Emax model. Values for population ED50 (the dose duration required to achieve 50% of the fitted AUECmax value) decreased with increase in dermatologic corticosteroid product potency.
  
  
  CONCLUSIONS
  Acceptable model fits to all individual subject dose-response data were not achieved for any dermatologic corticosteroid product. However, population dose-responses were adequately described by the Emax model. On the basis of these data, the optimal dose duration used for comparison of multisource dermatologic corticosteroid products is recommended to be equal to the ED50 based on population modeling of pilot dose-response study data.
authors.affiliation: Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD 20855, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Singh
authors.forename: W P
authors.initials: WP
authors.lastname: Adams
authors.forename: L J
authors.initials: LJ
authors.lastname: Lesko
authors.forename: V P
authors.initials: VP
authors.lastname: Shah
authors.forename: J A
authors.initials: JA
authors.lastname: Molzon
authors.forename: R L
authors.initials: RL
authors.lastname: Williams
authors.forename: L K
authors.initials: LK
authors.lastname: Pershing
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D001499:Bayes Theorem; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008962:Models, Theoretical; D013810:Therapeutic Equivalency
chemical_list: D000305:Adrenal Cortex Hormones; D003879:Dermatologic Agents