Effect of Hepatic Impairment on the Pharmacokinetics of a Single Dose of TD-9855

Theravance Biopharma

Status and phase: Completed; Phase 1

Conditions: nOH; Symptomatic Neurogenic Orthostatic Hypertension

Treatments: Drug: Ampreloxetine

Study type: Interventional

Funder types: Industry

Identifiers

NCT04200573

0179

Details and patient eligibility

About

An open-label study to characterize the effects of mild, moderate, and severe Hepatic Impairment (HI) on the pharmacokinetics (PK) of ampreloxetine following a single oral dose in comparison with healthy volunteers with normal hepatic function.

Full description

This is a multicenter, non-randomized, open label, parallel group, single dose, 2-part study being conducted in adult subjects with mild, moderate, or severe HI (Child-Pugh Class A, B, and C), and in matching healthy subjects. The healthy matching group will be comparable to the corresponding hepatic impairment groups by matching subjects by weight (±20% of group mean), age (±10 years of group mean), and sex (equal ratios across groups).

The study will be conducted in two sequential parts:

In Part A, following a 28-day screening period, 6 subjects each with mild or moderate HI and 6 matching healthy subjects who meet eligibility criteria will be enrolled and administered a single Dose A (Day 1).

In Part B, following a 28-day screening period, 6 subjects with severe hepatic impairment will receive a single Dose A (Day 1). Furthermore, the Sponsor may choose to enroll up to 6 additional healthy subjects in Part B to ensure matching of subjects across all groups for weight, age, and sex is maintained.

Enrollment: 31 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

All Subjects:

• has a body mass index (BMI) of 19 to 40 kg/m2, inclusive, and weight of at least 55 kg.
• clinical labs within normal ranges
• creatinine clearance of >70 mL/min
• women must be non-pregnant and non-lactating, male and females must agree to highly effective methods of contraception
• additional criteria apply

Subjects with Impaired Hepatic Function additional criteria:

• Subject has mild (Child-Pugh Class A [5 to 6 points]), moderate (Child-Pugh Class B [7 to 9 points]), or severe (Child-Pugh Class C [10-15 points]) liver disease
• has stable hepatic impairment defined as no clinically significant change in disease status within the last 30 days
• must be on a stable dose of medication and/or treatment regimen at least 30 days before dosing
• Additional inclusion criteria apply

Exclusion criteria

Subjects with normal hepatic function:

• history of reactions or hypersensitivity to ampreloxetine or known intolerance to other norepinephrine reuptake inhibitors (NRI) or serotonin norepinephrine reuptake inhibitors (SNRI).
• personal or family history of congenital long QT syndrome
• history of untreated closed angle glaucoma
• history of orthostatic hypotension or orthostatic tachycardia or a history of dizziness, lightheadedness or fainting, or a feeling of blacking out upon standing
• has used nephrotoxic or hepatotoxic medications 30 days before Day-2
• routinely uses more than 2 grams of acetaminophen daily
• has used tobacco-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, e cigarettes, vaporizers) within 3 months before Screening or has a positive cotinine result at Screening or Day -2
• used any CYP1A2 inhibitor or inducer within 7 days or 5 half lives, whichever is longer, prior to ampreloxetine dosing or requires concomitant use
• has used monoamine oxidase inhibitors (MAO-I) within 7 days or 5 half lives, whichever is longer, prior to ampreloxetine dosing or requires concomitant use
• additional exclusion criteria apply

Subjects with impaired hepatic function additional criteria:

• has severe ascites that could potentially interfere with respiratory function
• current severe hepatic encephalopathy
• history of liver transplantation, hepatocellular carcinoma, or acute liver disease
• has biliary liver cirrhosis
• has uncontrolled hypertension (SBP >180 mm Hg and DBP (Diastolic blood pressure) >110 mm Hg)
• has an abnormal ECG at Screening or Day -2, including QTcF (Fridericia's corrected QT Interval) >470 msec
• additional exclusion criteria apply

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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31 participants in 4 patient groups

Normal Hepatic Function

Experimental group

Description:

Ampreloxetine Dose A single dose administration to subjects with normal hepatic function

Treatment:

Drug: Ampreloxetine

Mild Hepatic Function

Experimental group

Description:

Ampreloxetine Dose A single dose administration to subjects with mild hepatic impairment

Treatment:

Drug: Ampreloxetine

Moderate Hepatic Function

Experimental group

Description:

Ampreloxetine Dose A single dose administration to subjects with moderate hepatic impairment

Treatment:

Drug: Ampreloxetine

Severe Hepatic Function

Experimental group

Description:

Ampreloxetine Dose A single dose administration to subjects with severe hepatic impairment

Treatment:

Drug: Ampreloxetine