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

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

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.

Keywords: Ampreloxetine; Autonomic failure; Neurogenic orthostatic hypotension; Norepinephrine reuptake inhibitor; Pharmacokinetics; Pharmacology.

Conflict of interest statement

Drs. Kanodia, Lo, Norcliffe-Kaufmann and Bourdet are employees of Theravance Biopharma US, Inc. Dr. Vickery is an employee of Theravance Biopharma Ireland Limited.

Figures

Fig. 1
Fig. 1
Ampreloxetine concentration and exposure: a mean ± SD plasma ampreloxetine concentrations (ng/mL) following daily oral administration of ampreloxetine for up to 20 weeks (Part C; dose levels combined for each sampling day/time—semi-log scale). Day 140 was the last day of dosing. Plasma concentrations of ampreloxetine (some below the limit of quantitation) were detected at week 22 (day 155) owing to incomplete washout. b Scatter plot of the individually predicted ampreloxetine steady-state exposures (area under the concentration–time curve from 0 to 24 h [AUC0–24]) vs. age and renal function (estimated glomerular filtration rate [eGFR]) of all patients
Fig. 2
Fig. 2
Pharmacokinetics of ampreloxetine: scatter plot of the change from time-matched baseline plasma DHPG vs. ampreloxetine concentrations with corresponding fit to maximum effect (Emax) relationship. DHPG 3,4-dihydroxyphenylglycol
Fig. 3
Fig. 3
Pharmacodynamics of ampreloxetine: a Shows significant increase in plasma NE concentration post-ampreloxetine. b Shows significant decrease in plasma DHPG concentrations post-ampreloxetine. c Shows increase in the ratio of NE to DHPG concentrations. All data are pre-dose and after 4 weeks of open-label treatment at a median dose of 10 mg per day (day 29). NE norepinephrine, DHPG 3,4-dihydroxyphenylglycol. Statistical significance was determined with a ratio paired t test
Fig. 4
Fig. 4
Effect on supine blood pressure. Scatter plot of the change from baseline in supine systolic blood pressure vs. individually predicted ampreloxetine exposures (AUC0–24), with corresponding linear fit showing no relationship. AUC0–24, area under the concentration–time curve from 0 to 24 h. DHPG 3,4-dihydroxyphenylglycol, SBP systolic blood pressure

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