effect of hepatic impairment on the pharmacokinetics of a single dose of td-9855

Conditions: Symptomatic Neurogenic Orthostatic Hypertension; nOH

Summary: 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.

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.

Eligibility criteria:
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

Keywords: symptomatic neurogenic orthostatic hypertension hepatic impairment