PURPOSE: 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.
PURPOSE: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: Mei-Ling Chen; Vinod P Shah; Derek Ganes; Kamal K Midha; James Caro; Prabu Nambiar; Mario L Rocci; Avinash G Thombre; Bertil Abrahamsson; Dale Conner; Barbara Davit; Paul Fackler; Colm Farrell; Suneel Gupta; Russell Katz; Mehul Mehta; Sheldon H Preskorn; Gerard Sanderink; Salomon Stavchansky; Robert Temple; Yaning Wang; Helen Winkle; Lawrence Yu Journal: AAPS J Date: 2010-05-04 Impact factor: 4.009
Authors: Hao-Jie Zhu; Kennerly S Patrick; Arthur B Straughn; Owen T Reeves; Hilary Bernstein; Jian Shi; Heather J Johnson; Joshua M Knight; Aaron T Smith; Robert J Malcolm; John S Markowitz Journal: J Clin Psychopharmacol Date: 2017-08 Impact factor: 3.153
Authors: Nathan S Teuscher; Akwete Adjei; Robert L Findling; Laurence L Greenhill; Robert J Kupper; Sharon Wigal Journal: Drug Des Devel Ther Date: 2015-05-26 Impact factor: 4.162