1501 SANCTURA XR A MUSCARINIC ANTAGONIST RESISTS TRANSPORT (SMART) ACROSS THE BLOOD-BRAIN BARRIER (BBB): A PROSPECTIVE NEUROCOGNITIVE, BIODISTRIBUTION AND PHARMACOKINETIC STUDY OF EXTENDED RELEASE TROSPIUM CHLORIDE (TRCL)

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Female Urology I1 Apr 20101501 SANCTURA XR A MUSCARINIC ANTAGONIST RESISTS TRANSPORT (SMART) ACROSS THE BLOOD-BRAIN BARRIER (BBB): A PROSPECTIVE NEUROCOGNITIVE, BIODISTRIBUTION AND PHARMACOKINETIC STUDY OF EXTENDED RELEASE TROSPIUM CHLORIDE (TRCL) David Staskin, Gary Kay, Howard B. Goldman, John Ling, Kavitha Bashi, and Michael G. Oefelein David StaskinDavid Staskin Boston, MA More articles by this author , Gary KayGary Kay Tampa, FL More articles by this author , Howard B. GoldmanHoward B. Goldman Cleveland, OH More articles by this author , John LingJohn Ling Irvine, CA More articles by this author , Kavitha BashiKavitha Bashi Irvine, CA More articles by this author , and Michael G. OefeleinMichael G. Oefelein Irvine, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1239AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Anti-muscarinic treatment of overactive bladder (OAB) has been reported to cause clinically relevant impairment of CNS function, and preclinical data strongly support the different propensities of OAB drug to cross the BBB (tertiary > quaternary amine). The specific aims of this study are: 1) to determine if TrCl crosses the BBB and 2) to determine if TrCl demonstrates a clinically significant memory effect. METHODS This is an open-label, non-comparator, evaluation of TrCl XR to penetrate the BBB at plasma steady state (Day 10). TrCl levels (time 0, 2, 5, 7, 12 and 24 hr post dose) in cerebrospinal fluid (CSF) and steady-state (day 10) peak and trough plasma levels (time 0, 5 and 24 hr) were measured in non-demented elderly (mini-mental state score > 25) human volunteers (n=12) 65-75 years of age (NCT00863551). Pre-TrCl dose and day 10 post-TrCl dose testing {Hopkins Verbal Learning Test-Revised (HVLT-R)} were compared using a reliable change index (RCI) to assess if any study subject shows evidence of a change in learning or memory. RESULTS Study subjects (mean age=68ys) reported no serious adverse events. The primary outcome (TrCl concentration in CSF at steady state peak plasma concentration 5 hours post dose) achieved undetectable TrCl concentration (<40 pg/ml) despite measureable peak plasma steady state values (Cmax=964 pg/mL, AUC=18,600 pg hr/mL). A total of 72 CSF samples were evaluated all of which fell below the BLQ (<40 pg/ml) for TrCl. The secondary end point (RCI pre- and 10 days post-dose neurocognitive measurements HVLT-R: total recall=-1.5, and delayed recall-0.25) revealed minimal improvement, but no clinically meaningful net drug effect. CONCLUSIONS TrCl is undetectable at multiple time points in the CSF of elderly OAB patients despite day 10 steady state peak plasma TrCl levels. No change in memory as assessed by the RCI of the HVLT-R was identified. These pharmacological and behavioral results support a lack of CNS penetration and clinical CNS safety in a neuro-cognitively vulnerable elderly OAB population. Parameter Mean ± SD CV% Minimum Maximum Median PLASMA Cmax(pg/mL) 964±440 45.7 385 1820 787 Tmax (hr) 8.17±7.40 90.6 5 24 5 Cmin(pg/mL) 503±329 65.3 158 1210 455 Tmin (hr) 6±10.9 181 0 24 0 AUC0-24 (pg*hr/mL) 18600±9110 49.0 7800 39000 14100 CSF AUC0-24 (pg*hr/mL) 0 0 <40 <40 0 © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e578-e579 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Staskin Boston, MA More articles by this author Gary Kay Tampa, FL More articles by this author Howard B. Goldman Cleveland, OH More articles by this author John Ling Irvine, CA More articles by this author Kavitha Bashi Irvine, CA More articles by this author Michael G. Oefelein Irvine, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...