CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis. (3rd July 2022)

• Record Type: Journal Article
• Authors: Takahashi, Yusuke; Ohashi, Nobuhiko; Takasone, Ken; Yoshinaga, Tsuneaki; Yazaki, Masahide; Roberts, Michael; Glidden, Paul F.; Sekijima, Yoshiki
• Is Part Of: Amyloid. Volume 29:Number 3(2022)
• Page Start: 190
• Page End: 196
• Publication Date: 2022-07-03
• Subjects: Hereditary ATTR amyloidosis -- transthyretin -- tolcapone -- cerebrospinal fluid -- cerebral amyloid angiopathy; Amyloidosis -- Periodicals; 616.3995
• DOI: 10.1080/13506129.2022.2056011
• Languages: English
• ISSNs: 1350-6129

Abstract

Abstract: Purpose: To investigate the effect of tolcapone on cerebrospinal fluid (CSF) transthyretin (TTR) tetramer stability in patients with hereditary transthyretin (ATTRv) amyloidosis. Methods: A total of 9 patients were enrolled in the study (3 men, 50.3 ± 14.4 years old). Three patients had central nervous system (CNS) involvement. Patients were assigned to receive tolcapone 300 mg/day or 600 mg/day for 7 days. Plasma and CSF were collected at baseline and 2 h after the final tolcapone dose. Results: The mean CSF tolcapone and 3-O-Methyltolcapone (3-OMT) concentration were 39.4 ± 36.3 ng/mL and 26.0 ± 4.9 ng/mL, respectively, after 7 days of tolcapone dosing. Tolcapone and 3-OMT were detected in the CSF of patients with or without CNS symptoms. The mean total study drug (tolcapone + 3-OMT) to TTR molar ratio in CSF was 1.15 ± 0.59. Orally administered tolcapone significantly increased CSF TTR concentration and decreased monomer content under semi-denaturing conditions. Eight adverse events (AEs) were reported in 6 patients. All AEs were mild in severity and resolved. Conclusions: Tolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis.