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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Alzheimers+Res+Ther 2014 ; 6 (2): 19 Nephropedia Template TP
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Modulation of ?-amyloid by a single dose of GSK933776 in patients with mild Alzheimer?s disease: a phase I study #MMPMID24716469
Leyhe T; Andreasen N; Simeoni M; Reich A; von Arnim CA; Tong X; Yeo A; Khan S; Loercher A; Chalker M; Hottenstein C; Zetterberg H; Hilpert J; Mistry P
Alzheimers Res Ther 2014[]; 6 (2): 19 PMID24716469show ga
Introduction: In this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-?-amyloid (anti-A?) monoclonal antibody GSK933776 in patients with mild Alzheimer?s disease and mild cognitive impairment. A? and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between A? levels and A? modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed. Methods: This trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n?=?6/group). The time course of plasma and CSF concentrations of GSK933776 and A? was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed. Results: Following administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF A?1?42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total A?18?35 and A?4228?42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose?response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter. Conclusion: GSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the A? changes following single-dose administration of GSK933776. Trial registration: ClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011