Objective: To characterize the Phase 2 pharmacokinetics (PK) and pharmacodynamics (PD) of ampreloxetine in patients with nOH and provide dosing recommendations for special populations in Phase 3.

Background: Ampreloxetine may prove beneficial for the treatment of primary autonomic failure by preventing norepinephrine (NE) reuptake and increasing blood pressure (BP) to provide relief from the symptomatic effects of nOH.

Method: A population PK model of ampreloxetine was developed using plasma concentration-time data from two Phase 1 studies in healthy volunteers (n=68) and three Phase 2 studies in ADHD (n=192), fibromyalgia (n=239) and nOH (n=31). The influence of sex, age, weight, creatinine clearance (CrCl), liver function and smoking status were tested as PK covariates. The relationship between ampreloxetine exposure and plasma biomarkers of norepinephrine reuptake (NE and its metabolite, DHPG) and supine systolic BP was evaluated.

Results: Ampreloxetine PK was best described using a two-compartment model with slow elimination and a terminal half-life of 30-40hr. Patients with nOH had similar PK characteristics as those observed in healthy volunteers and other patient populations. PK was not affected by age, CrCl, liver function or food intake. Sex and smoking status were statistically significant covariates for ampreloxetine exposure with ~33% lower exposures in men vs. women and ~33% lower exposures in smokers vs. nonsmokers. Increased exposure to ampreloxetine resulted in decreased DHPG concentrations and increased ratios of NE to DHPG. No relationship was observed between drug exposure and supine hypertension.

Conclusion: Phase 2 PK and PD properties of ampreloxetine are consistent with NE reuptake inhibition at tolerable dose levels in patients with nOH and support further evaluation in Phase 3. Ampreloxetine will be administered in Phase 3 studies without regard to food, age, or renal function [CrCL > 30 mL/min]. Even though sex and smoking status influence ampreloxetine PK, the impact is modest and dose modifications are not recommended for Phase 3 studies. Near maximal PD effects indicative of optimal NE transporter reuptake inhibition were observed at plasma concentrations associated with dose levels of 10 mg QD supporting selection of this dose for future studies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/population-pharmacokinetics-and-pharmacodynamics-of-ampreloxetine-td-9855-in-patients-with-neurogenic-orthostatic-hypotension-noh/