phase i study of linerixibat in adults with moderate hepatic impairment and healthy controls

Conditions: Pruritus

Summary: this is a phase 1, open-label, single-dose study in adults with moderate hepatic impairment (defined as child-pugh b cirrhosis) and matched healthy control participants with normal hepatic function. all participants in both cohorts (moderate hepatic impairment and matched healthy controls) will receive a single dose of the study drug, linerixibat. the purpose of this study is to assess the effect of hepatic impairment on the pharmacokinetics (pk) and safety of linerixibat.


Eligibility criteria:
inclusion criteria: all participants: * age: 18 to 75 years of age (inclusive). * weight greater than (\>) 45 kilograms (kg) and body mass index (bmi) 18.5 - 40 kg per square meter (kg/m\^2) (inclusive). * male and female- a female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies; not a woman of childbearing potential (wocbp) or a wocbp who agrees to follow contraceptive guidance during the treatment period and until at least 4 weeks after the last dose of study treatment. * participant capable of giving signed informed consent. participants with moderate hepatic impairment (cohort 1): * moderate hepatic impairment (of any etiology) and clinically stable for at least 1 month prior to screening. * child-pugh score of 7-9. * previous confirmation of liver cirrhosis confirmed by either- liver biopsy, imaging technique, or noninvasive liver assessment consistent with cirrhosis. * hepatic impairment needs to be chronic (\>6 months), stable. matched healthy control participants (cohort 2): * participants will be matched by age plus or minus (±)10 years to a corresponding participant in the hepatic impairment group. age should remain between 18 and 75 years of age (inclusive). * participants will be matched by total body weight ±15 percentage (%) to a corresponding participant in the hepatic impairment group. * participants will be matched by gender and race to a corresponding participant in the hepatic impairment group. * healthy participant as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and ecg. exclusion criteria: all participants: * participants are excluded from the study if any of the following medical conditions apply: * history of cholecystectomy, current symptomatic cholelithiasis or inflammatory gallbladder disease. * significant history of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data. * any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history review), clinical laboratory tests, or 12-lead ecg. * current clinically significant diarrhea. * history of gastrointestinal surgery with ileal resection or ileal bypass at any time. * any malignancy within the past 5 years except for basal cell or squamous cell carcinoma of the skin disease for 3 years. * participants with unstable cardiac function or participants with uncontrolled hypertension. * any current medical or psychiatric condition, clinical or laboratory abnormality, or examination finding which may affect study compliance or investigational procedures or possible consequences of the study. * administration of any other ileal bile acid transport (ibat) inhibitor (including linerixibat) in the 3 months prior to screening. * for healthy participants, past or intended use of over the counter or prescription medication, including vitamins and dietary or herbal supplements) within 7 days prior to the first dose of study medication. * current enrolment in a clinical trial or recent participation in a clinical trial and has received an investigational product within the following time-period prior to study drug administration in the current study: 30 days. * positive pregnancy test at screening or at day -1 in women of childbearing potential. * positive human immunodeficiency virus (hiv) antibody test. * healthy control participant has corrected interval using the fridericia's qt correction formula (qtcf) \>450 millisecond (msec); or participant with hepatic impairment has a baseline qtcf \>480 msec on ecg. * regular use of known drugs of abuse or history of drug abuse or dependence within 6 months of the study. * moderate (or greater) alcohol consumption defined as one standard drink per day for women and two drinks per day for men. * history of regular use of tobacco or nicotine-containing products. * positive drug/alcohol screen at screening or at day -1. * where participation in the study would result in donation of blood or blood products more than 500 milliliter (ml) within a 56-day period. * unwillingness or inability to follow the procedures outlined in the protocol. * sensitivity to any of the study interventions, or components thereof, or drug or other allergy that contraindicates participation in the study. participants with hepatic impairment (cohort 1): * history of gastric or oesophageal variceal bleeding within the past 6 months and for which varices have not been adequately treated medically or endoscopically. * grade 3 ascites (large ascites with marked abdominal distension) refractory to medical therapy. * refractory hepatic encephalopathy as judged by the investigator. * child-pugh score of 10 or higher or child-pugh score of 6 or lower. * hepatopulmonary or hepatorenal syndrome and history of liver transplantation. * evidence of active infection, including spontaneous bacterial peritonitis. * confirmed hepatocellular carcinoma (hcc) or biliary cancer. * alanine amino transferase (alt) value \>3 x upper limit of normal (uln). * platelet count less than (\<) 50,000/microliter (μl). matched healthy control participants (cohort 2): * current or chronic history of liver disease or known hepatic or biliary abnormalities and/or confirmed hepatocellular carcinoma or biliary cancer. * screening alt or aspartate aminotransferase (ast) above the upper limit of normal (uln). * elevated bilirubin above the uln unless this is due to underlying gilbert's syndrome. * presence of hepatitis b surface antigen (hbsag) at screening or within 3 months prior to first dose of study intervention. * positive hepatitis c antibody ribonucleic acid (rna) test result at screening or within 3 months prior to first dose of study intervention.

Keywords: linerixibat pruritus gsk2330672 pharmacokinetics primary biliary cholangitis hepatic impairment liver cirrhosis