Pharmacokinetics, Safety, and Tolerability of DA-302168S Tablets in Participants With Hepatic Impairment and Normal Hepatic Function

Prior treatment

• History of chronic pancreatitis, or acute pancreatitis within 3 months before ICF signing.
• History of acute gallbladder disease within 3 months before ICF signing.
• Any malignancy within 5 years before ICF signing (except basal cell carcinoma treated curatively and considered cured, and participants with prior liver cancer surgery who have been stable for ≥2 years).
• Participation in any clinical trial within 3 months before screening (except signing ICF only without drug or device intervention), or last dose of investigational drug in a prior trial less than 5 half-lives before screening.
• Severe hypoglycemia within 3 months before screening.
• Blood donation or significant blood loss (≥400 mL) within 3 months before screening or from screening to first dosing, or planned blood donation during the study.
• Within 3 months before screening, smoking \>5 cigarettes/day or habitual use of nicotine-containing products, or unable to abstain during the study.
• Consumption of any grapefruit-rich beverages/foods within 7 days before first dosing; or unwilling to stop grapefruit-rich beverages/foods during the study.
• Vaccination within 30 days before dosing, or planned vaccination within 30 days after dosing.

Other illness

• Within 1 year before ICF signing, history of serious diseases of the cardiovascular, neuropsychiatric, gastrointestinal, respiratory, urinary, or endocrine systems (e.g., acute myocardial infarction, major depression, gastric ulcer, uremia).
• As judged by the investigator, presence at screening of dysphagia, or any disease/condition that may affect drug absorption, distribution, metabolism, or excretion, such as active inflammatory bowel disease, gastrectomy, any intestinal resection, etc.
• History of allergic diseases (e.g., asthma, urticaria, eczema/dermatitis) or known intolerance/allergy to glucagon-like peptide-1 receptor (GLP-1R) agonists.
• Major surgery within 1 year before screening \[defined as surgery on intracranial, thoracic, abdominal, pelvic, or limb organs causing major tissue trauma and requiring long-term recovery (e.g., organ transplantation, cardiac surgery, joint replacement)\], or planned surgery during the study; or history of liver transplantation.
• History of drug abuse within 3 years before screening (e.g., morphine, ketamine, THC acid, methamphetamine, MDMA, cocaine) or positive baseline urine drug screen.
• History of alcohol abuse within 1 year before screening (i.e., \>14 standard units/week for males, \>7 for females; 1 standard unit = 14 g alcohol, e.g., 360 mL beer, 45 mL 40% spirits, or 150 mL wine), or positive baseline alcohol breath/blood test, or unable to abstain during the study.
• History of needle/blood phobia, difficulty with blood collection, or inability to tolerate venipuncture.
• Any other condition that, in the investigator's opinion, makes the participant unsuitable for the study.
• Exclusion criteria for normal hepatic function group:
  • History of chronic liver disease, including hepatitis, hepatitis B, or hepatitis C, or positive HBsAg/HCV antibody at screening;
  • Positive Treponema pallidum antibody;
  • Screening diastolic BP ≥90 mmHg or systolic BP ≥140 mmHg (if so, measure 2 additional times and use the mean of 3 measurements);
  • Use of any medication within 28 days or 5 elimination half-lives (whichever is longer) before first dosing, including prescription drugs, OTC drugs, herbal medicines, Chinese patent medicines, or nutritional supplements.

Lab values

• History or family history of medullary thyroid carcinoma, thyroid C-cell hyperplasia, or multiple endocrine neoplasia type 2; or screening serum calcitonin ≥50 ng/L.
• Exclusion criteria for hepatic impairment group:
  • Liver cancer (except participants stable ≥2 years after prior surgery), hepatorenal syndrome, or limited life expectancy (defined as \<1 year for the hepatic impairment cohort);
  • Cirrhosis with gastrointestinal bleeding within 3 months before screening that has not been treated with endoscopic ligation and sclerotherapy;
  • Active syphilis at screening \[positive T. pallidum antibody plus positive TRUST or RPR\], active hepatitis C \[anti-HCV positive and HCV RNA positive\], active hepatitis B \[HBsAg positive, no antiviral treatment, and HBV DNA positive\];
  • Drug-induced liver injury or acute liver injury of any cause;
  • Signs of clinically active grade 3 or 4 hepatic encephalopathy at screening;
  • Severe ascites and/or pleural effusion; if the investigator judges the participant is clinically stable, enrollment may be allowed;
  • Poorly controlled BP at screening (systolic ≥160 mmHg or diastolic ≥100 mmHg; if so, measure 2 additional times and use mean of 3 measurements); may enroll after BP is stable on medication for at least 1 week;
  • Screening ALT or AST \>5× ULN; one repeat test may be allowed if needed to assess eligibility;
  • Serum alpha-fetoprotein (AFP) \>20 ng/mL;
  • Abnormal prothrombin \> ULN;
  • Use of albumin within 1 month before screening;
  • Use of any drug that may affect DA-302168 PK within 7 days or 5 half-lives (whichever is longer) before first dosing, including prescription, OTC, herbal, Chinese patent medicines, or nutritional supplements;
  • Use of any drug that may worsen hepatic impairment or drugs with unknown composition within 28 days or 5 half-lives (whichever is longer) before first dosing, including prescription, OTC, herbal, Chinese patent medicines, or nutritional supplements.

Other

• Special dietary requirements and unable to accept the standardized diet.
• Unable to avoid strenuous exercise or other behaviors that may affect PK parameters from 48 h before dosing through the entire study.
• Pregnant or breastfeeding women.
• Participant is an investigator or other related study staff for this project.

• Age 18-70 years inclusive at ICF signing; male or female. Age matching (±10 years) between normal hepatic function and hepatic impairment groups; sex matching as much as possible (±1 participant/sex).
• Screening weight/BMI: males ≥50.0 kg, females ≥45.0 kg; BMI 19.0-30.0 kg/m² inclusive. Weight matching (±10 kg) between groups.
• Women and men of childbearing potential must agree to use reliable contraception for themselves and their partners during the study and for 90 days after dosing (see Appendix 4), and must not donate sperm or eggs/oocytes for assisted reproduction.
• Able to understand the study procedures and methods; voluntarily sign the ICF; willing to strictly follow protocol requirements and complete related procedures.
• Normal hepatic function group:
  • No clinically significant abnormalities in screening clinical laboratory results, vital signs, 12-lead ECG, or physical examination, as judged by the investigator.
  • No known or suspected hepatic impairment at screening; screening AST and ALT \< ULN.
• Hepatic impairment group:
  • Mild or moderate hepatic impairment by Child-Pugh classification due to viral hepatitis, alcoholic liver disease, non-alcoholic liver disease, schistosomal liver disease, or autoimmune hepatitis (excluding primary biliary cirrhosis).
  • Stable disease with no clinically significant change within 28 days before screening (e.g., no worsening of hepatic impairment symptoms, total bilirubin or prothrombin time not worsened by \>20%). Note: Additional screening tests may be performed if needed; external test results may be accepted for preliminary comparison at the investigator's discretion.
  • If receiving treatment for hepatic impairment or other comorbidities before screening, treatment must have been stable for ≥4 weeks and remain stable during the study.