Impact of release mechanism on the pharmacokinetic performance of PAUC metrics for three methylphenidate products with complex absorption.
OBJECTIVE
Investigate the performance of partial area under the drug concentration-time curve (PAUC) metrics (0-3 h) and (3-24 h), for Concerta, Ritalin LA and Focalin XR (different Methylphenidate modified-release formulations). The metrics have been chosen as additional BE metrics for Ritalin LA by the FDA to establish BE for these products due to the early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD).


METHODS
Two-stage analysis was performed on plasma data for the methylphenidate modified-release products. Simulations using the fitted parameters determined how changes in fast absorption rate constant k0fast, and slow absorption rate constant KAslow affected curve shape and BE determination using Cmax, AUCINF and PAUC.


RESULTS
Sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in k0fast and Kaslow were product dependent. Focalin XR mean PAUC(test)/PAUC(reference) ratios for PAUC0-3 h and PAUC3-24 h were most responsive to changes in k0Fast and Kaslow than Concerta and Ritalin LA. The PAUC(test)/PAUC(reference) ratios for (0-3 h) were not responsive to changes to Kaslow. Concerta PAUC (3-24 h) ratios were responsive to changes in Kaslow at ratios less than 1.


CONCLUSIONS
Response to PAUC(0-3 h) in the formulations was greater for k0fast than was PAUC(3-24) to changes in KAslow.
Food and Drug, Silver Spring, Maryland, USA, andre.jackson@fda.hhs.gov.
Andre
A
Jackson
D000042:Absorption; D019540:Area Under Curve; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018592:Cross-Over Studies; D006801:Humans; D008774:Methylphenidate / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D008774:Methylphenidate