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

Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin MA, Hinder M, Jhee S, Gevorkyan H, Rajman I - Br J Clin Pharmacol (2016)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.

No MeSH data available.


Related in: MedlinePlus

Individual subject LBQ657 concentrations vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily, (A) plasma and (B) cerebral spinal fluid. Left‐hand graph of each panel is a linear plot with an expanded time scale, right‐hand graph of each panel is a semi‐logarithmic plot
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bcp12861-fig-0003: Individual subject LBQ657 concentrations vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily, (A) plasma and (B) cerebral spinal fluid. Left‐hand graph of each panel is a linear plot with an expanded time scale, right‐hand graph of each panel is a semi‐logarithmic plot

Mentions: Following oral administration of LCZ696, peak concentrations (Cmax) of sacubitril, LBQ657 and valsartan were reached in plasma at median tmax times of 1 h, 2 h and 1 h, respectively (Table 4). In contrast to steady‐state PK of LCZ696 in plasma, the concentration of LBQ657 in CSF increased slowly, reaching Cmax in a median tmax time of 8 h (Table 4, Figure 3). At steady‐state, mean Cmax and trough CSF concentrations (Ctrough) of LBQ657 were 19.2 ng ml‐1 and 13.2 ng ml‐1, respectively. The CSF : plasma ratio of LBQ657 exposure (AUC(0,τ,ss)) was estimated to be 0.002825. Since sacubitril and valsartan do not inhibit neprilysin, CSF concentrations of these LCZ696 analytes were not measured.


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

Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin MA, Hinder M, Jhee S, Gevorkyan H, Rajman I - Br J Clin Pharmacol (2016)

Individual subject LBQ657 concentrations vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily, (A) plasma and (B) cerebral spinal fluid. Left‐hand graph of each panel is a linear plot with an expanded time scale, right‐hand graph of each panel is a semi‐logarithmic plot
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834603&req=5

bcp12861-fig-0003: Individual subject LBQ657 concentrations vs. time on day 14 following oral administration of LCZ696 at 400 mg once daily, (A) plasma and (B) cerebral spinal fluid. Left‐hand graph of each panel is a linear plot with an expanded time scale, right‐hand graph of each panel is a semi‐logarithmic plot
Mentions: Following oral administration of LCZ696, peak concentrations (Cmax) of sacubitril, LBQ657 and valsartan were reached in plasma at median tmax times of 1 h, 2 h and 1 h, respectively (Table 4). In contrast to steady‐state PK of LCZ696 in plasma, the concentration of LBQ657 in CSF increased slowly, reaching Cmax in a median tmax time of 8 h (Table 4, Figure 3). At steady‐state, mean Cmax and trough CSF concentrations (Ctrough) of LBQ657 were 19.2 ng ml‐1 and 13.2 ng ml‐1, respectively. The CSF : plasma ratio of LBQ657 exposure (AUC(0,τ,ss)) was estimated to be 0.002825. Since sacubitril and valsartan do not inhibit neprilysin, CSF concentrations of these LCZ696 analytes were not measured.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Translational Medicine, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.

No MeSH data available.


Related in: MedlinePlus