The effect of LCZ696 (sacubitril/valsartan) on amyloid‐β concentrations in cerebrospinal fluid in healthy subjects

Autor: Marie-Anne Valentin, Thomas Langenickel, Chiaki Tsubouchi, Markus Hinder, Hakop Gevorkyan, Stanford Jhee, Surya Ayalasomayajula, Iris Rajman, Parasar Pal
Rok vydání: 2016
Předmět:
Zdroj: British Journal of Clinical Pharmacology
ISSN: 1365-2125
0306-5251
DOI: 10.1111/bcp.12861
Popis: Aims LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid‐β (Aβ). Its inhibition may increase Aβ levels. The potential exists that treatment of LCZ696, through the inhibition of neprilysin by LBQ657 (an LCZ696 metabolite), may result in accumulation of Aβ. The aim of this study was to assess the blood–brain‐barrier penetration of LBQ657 and the potential effects of LCZ696 on cerebrospinal fluid (CSF) concentrations of Aβ isoforms in healthy human volunteers. Methods In a double‐blind, randomized, parallel group, placebo‐controlled study, healthy subjects received once daily LCZ696 (400 mg, n = 21) or placebo (n = 22) for 14 days. Results LCZ696 had no significant effect on CSF AUEC(0,36 h) of the aggregable Aβ species 1–42 or 1–40 compared with placebo (estimated treatment ratios 0.98 [95% CI 0.73, 1.34; P = 0.919] and 1.05 [95% CI 0.82, 1.34; P = 0.702], respectively). A 42% increase in CSF AUEC(0,36 h) of soluble Aβ 1–38 was observed (estimated treatment ratio 1.42 [95% CI 1.05, 1.91; P = 0.023]). CSF levels of LBQ657 and CSF Aβ 1–42, 1–40, and 1–38 concentrations were not related (r 2 values 0.022, 0.010, and 0.008, respectively). Conclusions LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1–42 and 1–40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin. The clinical relevance of the increase in soluble CSF Aβ 1–38 is currently unknown.
Databáze: OpenAIRE
Externí odkaz: