TROSPIUM CHLORIDE IS UNDETECTABLE IN THE OLDER HUMAN CENTRAL NERVOUS SYSTEM

Abstract

To the Editor: Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) affects.1, 2 Memory deficits with oxybutynin and tolterodine have been reported.3-5 The available agents for the treatment of OAB are relatively lipophilic tertiary amines, which may be partially unionized at physiological pH. An exception is trospium chloride, which is a quaternary ammonium compound, which confers a permanent cationic charge at physiological pH. The resulting hydrophilicity limits the ability of trospium to cross the lipid cell membranes.6, 7 Hence, it would not be expected to penetrate into the human CNS.8, 9 An institutional review board–approved clinical trial (NCT00863551) was performed to determine whether trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. Twelve cognitively intact older adults (aged ≥65–75; median age 69) with OAB and stable comorbidities were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardized memory testing (Hopkins Verbal Learning Test Revised and Brief Visuospatial Memory Test Revised) was performed before and after the 10-day period.10 Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on Day 10 and assayed for trospium chloride. Predose (Day 0) and postdose (Day 10) results on the memory tests were compared using a reliable change index to assess meaningful change in learning or memory. Trospium chloride levels in the CSF samples of all participants were assay undetectable (<40 pg/mL) on Day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values (Figure 1). Repeat memory testing revealed no significant net drug effect on learning or recall. Plasma and cerebrospinal fluid (CSF) trospium concentration-time profiles on Day 10 after once-daily multiple dose oral administration of 60-mg extended-release trospium chloride capsules in older adult subjects (n=12). This is the first study to investigate the presence of an orally dosed OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures in older adults. Specifically, extended-release trospium chloride was not assay detectable in human CSF concurrent with peak steady-state plasma concentration, and participants concomitantly showed no decline in performance on tests of learning and memory over a 10-day period. The results of pharmacological and memory tests support the hypothesis of a lack of significant CNS penetration for the quaternary amine trospium chloride. Based on the quaternary amine structure and the corresponding cationic charge, it has been predicted that trospium chloride would not be able to cross the human blood–brain barrier (BBB).6-9 Because of the complexities of the aging human BBB, this concept required human clinical trial validation. This study is the first to support the lack of trospium chloride penetration in older adults with OAB and stable comorbid disease who are at risk for drug penetration across the BBB. The correlation of this pharmacokinetic finding with the memory test findings supports the pharmacodynamic antimuscarinic hypothesis; if an antimuscarinic does not cross the BBB, it should not cause cognitive impairment. Larger comparator trials are a logical next step in the evaluation and interpretation of these preliminary findings. Conflict of Interest: Funding provided by Allergan, LLC. Staskin: Received honorarium from and consultant for Allergan, Astella, Pfizer, and Watson; speakers' forum at Allergen, Astella, and Pfizer. Kay: Consultant for Allergan on study design, test administration, evaluation of CNS effects of antimuscarinics, and publications; received honoraria for consulting and training speakers. Consultant and speaker for Pfizer, Novartis. Consultant for Watson. Tannenbaum: Speaker and consultant for Allergan. Goldman: speaker for Pfizer, Astellas, Novartis, and Watson; consultant for Johnson and Johnson, Pfizer, and Allergan; investigator for Allergan. Bhashi and Ling: employees of Allergan, LLC, Pharmacology. Oefelein: employee of Allergan, LLC, Urology. Author Contributions: Staskin: study concept and design, analysis and interpretation of data, preparation of manuscript. Kay: study design, training of site staff to administer memory tests, quality assurance of collected data, interpretation of results, development of manuscript. Tannenbaum: analysis and interpretation of data, preparation of manuscript. Goldman: study design, data analysis, manuscript preparation. Oefelein: study design, conduct, monitoring, analysis of data, manuscript preparation. Bashsi and Ling: pharmacokinetics, bioanalytics, preparation of manuscript. Sponsor's Role: None.