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PK Study Comparing Upsher-Smith's Extended-Release Topiramate Formulation (USL255) With Topamax® Published Online In Epilepsia
Date:7/25/2011

MAPLE GROVE, Minn., July 25, 2011 /PRNewswire/ -- In a comparative pharmacokinetic (PK) study, Upsher-Smith Laboratories' USL255, a new, once-daily extended-release formulation of topiramate in development for the management of epilepsy in adults, was shown to be bioequivalent to twice-daily immediate-release topiramate (Topamax®*) in its extent of absorption.  Furthermore, USL255, administered with or without food, demonstrated a slower absorption profile compared with Topamax®.  The more consistent plasma profile of USL255 allows for once-daily dosing with diminished fluctuations in topiramate plasma levels.  The results of this study were published in the online edition of Epilepsia on July 20, 2011.

"In the study, this new topiramate extended-release formulation demonstrated less fluctuation between the peak and trough concentrations than immediate-release topiramate; thereby providing a relatively flat topiramate plasma concentration versus time profile that should allow for once-daily dosing.  Once-daily dosing may simplify topiramate therapy in adult epilepsy patients," said Larry Lambrecht, Pharm.D., first author.  "In theory, reducing fluctuations of plasma concentrations of antiepileptic drugs may also minimize potential concentration-related adverse events."

About the PK StudyThe randomized, open-label, cross-over study had three dosing periods separated by 21 days of washout between treatments. Thirty-six healthy adult volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax® (100 mg) administered 12 hours apart. Topiramate plasma samples were analyzed by liquid chromatography with tandem-mass spectroscopy.  

A single dose of USL255 was found to be bioequivalent to Topamax® in its extent of absorption; however, it had a slower extent of absorption as reflected by its later t(max) (time to reach peak plasma concentration) and t(1/2,eff) (effective half-life) values.  A median t(max) value of 20 and 24 hours after single dose indicates that topiramate absorption will continue throughout the 24-hour dosing interval in both fasted and fed conditions, respectively.  The plateau time (the time span in which topiramate plasma concentrations deviated from C(max) by less than 20%) of USL255 was three to four times longer than that of Topamax®.  

Mean +/- SD PK parameters of topiramate following a single dose of USL255 (200 mg) with or without food and Topamax® (100mg Q12h)PK ParameterUSL255 (fasted)N=35USL255 (fed)N=36Topamax®N=35t(max) (h)

Mean

Median19.5+/- 7.2

2022.7 +/- 4.3

241.4 +/- 1.1

1Effective half-life

t(1/2, eff) (h)55.7 +/- 19.972.5 +/- 15.437.1 +/- 6.5Plateau Time

12.1 +/- 4.0

8.0 +/- 3.3

2.6 +/- 1.9C(max)/C(trough)1.2 +/- 0.11.1 +/- 0.11.7 +/- 0.3USL255 is also the subject of an ongoing large, global Phase III clinical trial (PREVAIL) in which Upsher-Smith expects to demonstrate that it is effective and well-tolerated as adjunctive therapy in adult epilepsy patients with refractory partial-onset seizures.  Currently, patients completing the PREVAIL study are eligible to enroll in an open-label extension study to provide extended therapy and to capture additional long-term tolerability information.  Further information on the PREVAIL and open-label extension studies can be found at http://clinicaltrials.gov/ct2/show/NCT01142193?intr=%22USL255%22&rank=1; http://clinicaltrials.gov/ct2/show/NCT01191086?intr=%22USL255%22&rank=2  respectively.

About EpilepsyEpilepsy is a medical condition that produces seizures affecting a variety of mental and physical functions.  An estimated three million people in the U.S. have some form of epilepsy with about 200,000 new cases of epilepsy diagnosed each year.(1)

Upsher-Smith's Expanding CNS PipelineUpsher-Smith's central nervous system (CNS) pipeline includes a number of investigational drug programs.  In addition to USL255 (extended-release topiramate), USL is developing an intranasal midazolam (USL261), for the rescue treatment of seizures in patients on stable anti-epileptic drug regimens who require control of intermittent bouts of increased seizure activity, frequently referred to as seizure clusters.  Another program is USL260 (tonabersat), an investigational drug and first-in-class neuronal gap junction modulator which is also a potential treatment for epilepsy.  

About Upsher-SmithUpsher-Smith Laboratories, Inc., founded in 1919, is a rapidly growing, privately held pharmaceutical company that develops, manufactures, and markets prescription and consumer products.  Upsher-Smith's product portfolio focuses in the areas of women's health, dermatology, cardiology, and CNS diseases.  The company's focus is growing a CNS pipeline for diseases with significant unmet need, including epilepsy and Parkinson's disease.  To expand its CNS pipeline, Upsher-Smith seeks alliances and co-development programs, pursues licensing and acquisitions, and leverages its core competency in formulation development.  For more information, visit www.upsher-smith.com.

*Topamax® (immediate-release topiramate) is a registered trademark of Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals.

References(1) Epilepsy Foundation. Epilepsy and seizure statistics. Available at: http://www.epilepsyfoundation.org/about/statistics.cfm. Accessed May 18, 2011.


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