Arthur Lo1, Lucy Norcliffe-Kaufmann1,2, Ross Vickery3, David Bourdet1, Jitendra Kanodia4. 1. Clinical and Translational Pharmacology, Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. 2. Clinical Science, Neurology, Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. 3. Theravance Biopharma Ireland Limited, Dublin, Ireland. 4. Clinical and Translational Pharmacology, Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. jkanodia@theravance.com.
Abstract
PURPOSE: Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. METHODS: Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. RESULTS: Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6-9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). CONCLUSIONS: Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.
PURPOSE:Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. METHODS:Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. RESULTS: Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6-9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). CONCLUSIONS: Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.
Authors: Roy Freeman; Wouter Wieling; Felicia B Axelrod; David G Benditt; Eduardo Benarroch; Italo Biaggioni; William P Cheshire; Thomas Chelimsky; Pietro Cortelli; Christopher H Gibbons; David S Goldstein; Roger Hainsworth; Max J Hilz; Giris Jacob; Horacio Kaufmann; Jens Jordan; Lewis A Lipsitz; Benjamin D Levine; Phillip A Low; Christopher Mathias; Satish R Raj; David Robertson; Paola Sandroni; Irwin Schatz; Ron Schondorff; Julian M Stewart; J Gert van Dijk Journal: Clin Auton Res Date: 2011-04 Impact factor: 4.435
Authors: J R Shannon; N L Flattem; J Jordan; G Jacob; B K Black; I Biaggioni; R D Blakely; D Robertson Journal: N Engl J Med Date: 2000-02-24 Impact factor: 91.245