Comparative Pharmacodynamics and Plasma Concentrations of d-threo-Methylphenidate Hydrochloride After Single Doses of d-threo-Methylphenidate Hydrochloride and d,l-threo-Methylphenidate Hydrochloride in a Double-Blind, Placebo-Controlled, Crossover Laboratory School Study in Children With Attention-Deficit/Hyperactivity Disorder - 24/08/11
, JAMES SWANSON, Ph.D., SHARON HIRSCH, M.D., YVONNE OTTOLINI, Ph.D., MAGHSOUD DARIANI, M.S., MARK ROFFMAN, Ph.D., JEROME ZELDIS, M.D., THOMAS COOPER, M.A.ABSTRACT |
Objective: |
Methylphenidate has four optical isomers due to two asymmetries (erythro-threo and dextro-levo). The initial commercial formulation eliminated the erythro isomer, but the dextro-levo asymmetry was racemic, with equal amounts of d and l-threo isomers (d,l-MPH). Previous work has suggested that the d-threo isomer methylphenidate (d-MPH) rather than the l-threo isomer (l-MPH) is responsible for the clinical effects in children with attention-deficit/hyperactivity disorder (ADHD). This study compared the efficacy of acute equimolar doses of d-MPH and dl-MPH in reducing ADHD symptoms over an 8-hour period in a laboratory school setting and investigated the relationship of efficacy to plasma levels of MPH.
Method: |
Thirty-two children with ADHD enrolled in this double-blind, placebo-controlled, crossover study, and 31 completed the study. On seven separate occasions separated by at least 6 days, the children received a single morning dose of d-MPH (2.5, 5, or 10 mg), d,l-MPH (5, 10, or 20 mg), or placebo and then were observed in a laboratory classroom setting for 8 hours. At specified intervals, blinded observers rated behavior, and the children performed a computerized math test. The plasma levels of MPH were related to the response to study medication. The safety profiles of the two formulations were compared.
Results: |
For both formulations, the responses to both MPH preparations were dose related, the plasma concentrations of l-MPH were negligible and of d-MPH were indistinguishable, and clinical efficacy was highly correlated with plasma concentrations of d-MPH. The efficacy of the d-isomer was equivalent to the racemic preparation in reducing ADHD symptoms and increasing academic productivity.
Conclusions: |
The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.
Le texte complet de cet article est disponible en PDF.Key Words : attention-deficit/hyperactivity disorder, d,l-methylphenidate, d-methylphenidate, stimulant, pediatric
Plan
| Funding for this study was provided by Celgene, and d-methylphenidate is now available and marketed as Focalin™. Disclosure: Dr. Quinn receives research support and participates in clinical trials with Janssen, Eli Lilly, Shire, and Celltech and has also consulted with the same companies regarding advisory boards and studies. He is also on the speakers’ bureau of Veritas. Dr. Wigal has served as a consultant for Alza, Celltech, McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. She has received research support from Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. and also has served on the speakers’ bureau of Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. Dr. Swanson has served as a consultant for Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, Shire US Inc., and Targacept, Inc. He has received research support from Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. Dr. Swanson serves on the speakers’ bureau of Alza, Celgene, Celltech, Cephalon, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. Dr. Hirsch is on the speakers’ bureau of Eli Lilly and Company, McNeil Consumer & Specialty Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Shire US Inc. Mr. Dariani is currently President and CEO of Semorex Inc., a company involved in the development and commercialization of innovative point-of-use detection and diagnostic products. Before Semorex, Mr. Dariani was President of Focus Pharmaceuticals Inc., a specialty drug development company. Before Focus, Mr. Dariani was Vice President of Chiral Pharmaceuticals at Celgene Corporation. Mr. Dariani has no financial affiliation with either Celgene Corporation or Novartis Pharmaceuticals Corporation. Dr. Roffman is President of ClinSearch, Inc., a clinical trials site that is owned by Comprehensive NeuroScience. He is also President of MRCS, Inc. and is a consultant to Gel Med Sciences, a private biotech company and was a consultant to Celgene at the time that this research was conducted. Dr. Zeldis is the Chief Medical Officer and Vice President of Medical Affairs of Celgene Corporation. As such, he is salaried by Celgene and is a stockholder. In addition, he owns in his personal portfolio a variety of biopharmaceutical stocks including Allos, Johnson and Johnson, and Merck. He is on the Board of Directors of Semorex, a technology company. Mr. Cooper is a consultant to Bristol-Myers Squibb for their Aripiprazole product. |
Vol 43 - N° 11
P. 1422-1429 - novembre 2004 Retour au numéro
Article précédent
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