Pharmacokinetics of Ampreloxetine, a Norepinephrine Reuptake Inhibitor, in Healthy Subjects and Adults with Attention-Deficit/Hyperactive Disorder or Fibromyalgia Pain

Abstract

Background and objective: Ampreloxetine is a novel norepinephrine reuptake inhibitor in development for the treatment of symptomatic neurogenic orthostatic hypotension. The objectives of this analysis were to define the pharmacokinetics of once-daily oral ampreloxetine and provide dose recommendations for clinical development.

Methods: We fitted a population pharmacokinetic model to ampreloxetine plasma concentrations from single- and multiple-ascending dose trials in healthy subjects and two phase II studies in adult subjects with attention-deficit/hyperactive disorder or fibromyalgia at doses of 2-50 mg.

Results: Ampreloxetine pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. The terminal half-life was 30-40 h, resulting in sustained drug concentrations for the entire 24-h dosing interval at steady state. Covariates of age, weight, or renal impairment did not impact ampreloxetine exposure. Cytochrome P450 2D6 phenotype had no influence on ampreloxetine exposure. Sex and smoking status were identified as statistically significant covariates, suggesting a role for cytochrome P450 1A2 in the elimination of ampreloxetine. Despite statistical significance, differences in ampreloxetine exposure in male vs female subjects and smokers vs non-smokers were not clinically meaningful at the recommended dose. At the 10-mg dose, > 75% norepinephrine transporter inhibition and < 50% serotonin transporter inhibition are anticipated for adult subjects.

Conclusions: The population pharmacokinetic model effectively described the plasma concentration-time profile of ampreloxetine after single and multiple doses. Population pharmacokinetic/pharmacodynamic analysis justified using a fixed dosing regimen with no dose adjustments across a broad population and can be used to inform dosing strategies in future clinical studies.

Clinical trial registration: ClinicalTrials.gov identifier numbers NCT01693692 (fibromyalgia); NCT01458340 (attention-deficit/hyperactive disorder).

Conflict of interest statement

Jitendra Kanodia, Arthur Lo, R. Michael Baldwin, Richard A. Graham, and David L. Bourdet are current or former employees of Theravance Biopharma US, Inc.

Figures

Fig. 1

Mean plasma concentrations of ampreloxetine: a day 1 of single-ascending dose (SAD) study, b day 14 of multiple-ascending dose (MAD) study, and c attention-deficit/hyperactivity disorder study grouped by cytochrome P450 (CYP) 2D6 phenotype

Fig. 2

Effect of covariates on the model-predicted ampreloxetine exposure following repeated 10-mg once-daily dosing: a sensitivity plot comparing the effect of significant covariates, b grouped by disease state. Base, as represented by the black vertical line, refers to the predicted typical area under the concentration–time curve from time 0 to 24 h (AUC0–24) in a female non-smoker from the population pharmacokinetic model. The top horizontal bar with values at each end shows the 5th to 95th percentile AUC0–24 range across the entire population. The middle and lower horizontal bars represent the influence of a single categorical covariate on AUC0–24, with one subject created from each category with other covariates fixed at the typical values for the base subject. The solid black line denotes the median; the top and the bottom of the box denote the first and third quartiles; the whiskers denote 1.5 times the interquartile range. ADHD attention-deficit/hyperactivity disorder, AUCss AUC at steady state, CI confidence interval, FM fibromyalgia

Fig. 3

Predicted ampreloxetine steady-state pharmacokinetics and pharmacodynamics following repeated 10-mg and 5-mg doses: a area under the concentration–time curve (AUC). b Predicted brain norepinephrine transporter (NET) occupancy at an average plasma concentration of ampreloxetine. The solid black line denotes the median; the top and the bottom of the box denote the first and third quartiles; the whiskers denote 1.5 times the interquartile range