title: Use of partial AUC (PAUC) to evaluate bioequivalence--a case study with complex absorption: methylphenidate.
abstract: OBJECTIVE
  Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products.
  
  
  METHODS
  A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC.
  
  
  RESULTS
  The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased.
  
  
  CONCLUSIONS
  PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation & Research Food & Drug Administration, 10903 New Hampshire Ave, Silver Spring, Maryland 20993, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Fourie Zirkelbach
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Jackson
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Schuirmann
mesh_terms: D019540:Area Under Curve; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000097:blood* / Q000737:chemistry; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000737:chemistry*; D006801:Humans; D008774:Methylphenidate / Q000008:administration & dosage* / Q000097:blood* / Q000737:chemistry; D008954:Models, Biological; D013810:Therapeutic Equivalency
chemical_list: D000697:Central Nervous System Stimulants; D003692:Delayed-Action Preparations; D008774:Methylphenidate