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Clinical Autonomic Research

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01-06-2021 | Pharmacodynamics | Research Article

Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension

Authors: Arthur Lo, Lucy Norcliffe-Kaufmann, Ross Vickery, David Bourdet, Jitendra Kanodia

Published in: Clinical Autonomic Research | Issue 3/2021

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.

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Title: Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension
Authors: Arthur Lo
Lucy Norcliffe-Kaufmann
Ross Vickery
David Bourdet
Jitendra Kanodia
Publication date: 01-06-2021
Publisher: Springer Berlin Heidelberg
Keywords: Pharmacodynamics
Pharmacokinetics
Hypotension
Hypotension
Published in: Clinical Autonomic Research / Issue 3/2021
Print ISSN: 0959-9851
Electronic ISSN: 1619-1560
DOI: https://doi.org/10.1007/s10286-021-00800-x

2024 ASCO Annual Meeting

Springer Medicine

Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension

Abstract

Purpose

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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