Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients

Abstract

Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ≈2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggest that tafamidis can cross the CSF-blood and eye-blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers or TTR lowering drugs are essential to understand the clinical effect of our observations.

Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma

“…Tolcapone's black box warning aside, its 3 h half-life makes it very challenging to find a tolcapone dose and dosing regimen that can match the kinetic stabilisation imparted by other stabilisers during the sleep cycle [26]. The potency similarities revealed by our study suggest that other pharmacologic considerations, such as safety, adsorption and metabolism, pharmacokinetics, and the stabilisers' tissue distribution (tafamidis and tolcapone have meaningful exposure in the eyes and in the brain [44,45]) are also very important considerations for clinical use decisions.…”

Tafamidis is entering the clinical arena for the treatment of transthyretin‐related cardiomyopathy: certainties and unmet needs

“…3 The small molecule of tafamidis has the potential to cross the blood-brain barrier, but no more than 1.5% of the circulating drug reaches the cerebrospinal fluid. 15 Tafamidis has a slow elimination, with a mean half-life of approximately 59 h. Glucuronidation is the major metabolic pathway. Steady-state clearance of tafamidis is not affected in patients with renal impairment, but systemic exposure is reduced by approximately 40% in patients with moderate hepatic impairment.…”

“…Almost all circulating drug (>99.5%) is bound to plasma proteins 3 . The small molecule of tafamidis has the potential to cross the blood–brain barrier, but no more than 1.5% of the circulating drug reaches the cerebrospinal fluid 15 . Tafamidis has a slow elimination, with a mean half‐life of approximately 59 h. Glucuronidation is the major metabolic pathway.…”

Are we creating a new phenotype? Physiological barriers and ethical considerations in the treatment of hereditary transthyretin-amyloidosis

“…This might confront patients and caregivers with new challenges in the future. Out of the currently approved treatments, tafamidis is the only one that crosses the blood–brain barrier, but only minimally [ 22 ]. Previous studies have shown that CSF TTR is mainly produced in the choroid plexus [ 12 ], and can thereby not be influenced by hepatic TTR mRNA degradation.…”