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MICROMEDEX® Healthcare Series : Document Case 3:09-cv-00080-TMB Document 78-23 Filed 03/24/2010 Page 5 of 31 Page 5 of 105 1) The mean time to the first peak (tmax1) (1.5 hours) is similar to the tmax for the immediate-release formulation. The time to the second peak (tmax2) (6.5 hours) is slightly longer for the extended-release formulation given once-daily compared to the immediate-release formulation given in 2 doses 4 hours apart (Prod Info FOCALIN(TM) XR, 2005). 3) Area Under the Curve a) The AUC after administration of dexmethylphenidate hydrochloride extended-release tablets given once daily is equivalent to the same total dose of dexmethylphenidate hydrochloride immediate-release tablets given in 2 doses 4 hours apart; variability in AUC is similar between the extended- and immediate-release tablets with approximately a three-fold range in each (Prod Info FOCALIN(TM) XR, 2005). 2.3 ADME Absorption Distribution Metabolism Excretion Elimination Half-life 2.3.1 Absorption A) Dexmethylphenidate Hydrochloride 1) Bioavailability a) Oral, various: mean absolute bioavailability 22 to 25% (Prod Info FOCALIN(TM) XR, 2005). 1) Dexmethylphenidate is well absorbed after oral administration with approximately 90% recovered in the urine. However, due to first-pass metabolism, the mean absolute bioavailability when administered in various formulations was 22 to 25% (Prod Info FOCALIN(TM) XR, 2005). 2) Effects of Food a) immediate-release tablet, delayed absorption (Prod Info Focalinâ¢, 2001a). 1) In an unpublished study, administration of dexmethylphenidate with food had no significant effect on extent of absorption compared to the fasting state (based on peak plasma levels and AUC values); however, time to peak plasma levels was prolonged when given with food (mean, 2.9 versus 1.5 hours) (Prod Info Focalinâ¢, 2001a). Dexmethylphenidate can be given with or without food. b) extended-release tablet, unknown (Prod Info FOCALIN(TM) XR, 2005) 1) No food effect study was performed with the extended-release formulation; administration times relative to meals and meal composition may need to be individually titrated (Prod Info FOCALIN (TM) XR, 2005). 2) Effect of food: oral, racemic methylphenidate extended release tablets, following high fat breakfast, delayed absorption and second peak concentration is approximately 25% lower. Can be administered with or without food (Prod Info FOCALIN(TM) XR, 2005). 2.3.2 Distribution A) Distribution Sites 1) Dexmethylphenidate Hydrochloride a) Protein Binding 1) A specific value for dexmethylphenidate is unavailable. However, protein binding of racemic methylphenidate is minimal (12 to 15%) .(Prod Info FOCALIN(TM) XR, 2005) B) Distribution Kinetics 1) Dexmethylphenidate Hydrochloride a) Volume of Distribution 1) 2.65 L/kg (+/- 1.1 L/kg) (Prod Info FOCALIN(TM) XR, 2005). 2.3.3 Metabolism A) Metabolism Sites and Kinetics 1) Dexmethylphenidate Hydrochloride a) LIVER, extensive (Prod Info Focalinâ¢, 2001a). 1) The primary metabolic pathway is deesterification to the inactive metabolite d-ritalinic acid (dalpha-phenyl piperidine acetic acid) (Prod Info Focalinâ¢, 2001a). 2) Inhibition of cytochrome P450 isozymes was not observed with dexmethylphenidate in vitro (Prod Info Focalinâ¢, 2001a). 3) Bioconversion to l-dexmethylphenidate is negligible (Prod Info Focalinâ¢, 2001a) and of no Exhibit E.11, page 5 http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/pf.PrintReady 7/7/2009
