A Phase I Clinical Trial to Evaluate the Pharmacokinetic and Safety of Ammoxetine Hydrochloride Enteric-Coated Tablets in Participants With Mild Hepatic Impairment, Moderate Hepatic Impairment, and Normal Liver Function

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Inclusion criteria

Inclusion criteria

for participants with abnormal liver function (all 7 criteria must be met):

• Adults aged 18 ~ 75 years (inclusive), regardless of gender
• Body weight ≥ 45.0 kg (female) or ≥ 50.0 kg (male), body mass index (BMI) in the range of 19 ~ 32 kg/m2 (inclusive);
• Participants whose medical history, vital signs, physical examination, laboratory tests (hematology, blood biochemistry, urinalysis, coagulation function, infectious disease screening, and other relevant tests), Chest X-ray, abdominal color Doppler ultrasound, electroencephalogram (EEG), alpha-fetoprotein (AFP), plasma ammonia, abnormal prothrombin, and other examination must be deemed suitable for participation in this study by the investigator;
• Participants and their partners must use effective contraception (e.g., condoms, inert intrauterine devices, etc.) from 2 weeks prior to screening until 6 months after the end of the study, unless they have already undergone permanent sterilization procedures, such as bilateral tubal ligation or vasectomy; furthermore, they must not donate sperm or eggs.
• Participants must have not taken any medications within 2 weeks prior to screening, or must have been on a stable medication regimen for at least 4 weeks for the treatment of liver impairment and/or other comorbidities;
• Participants who have mild or moderate hepatic impairment according to the Child-Pugh classification, resulting from chronic hepatic insufficiency or cirrhosis caused by a history of primary liver disease (e.g., viral hepatitis, alcoholic liver disease, autoimmune hepatitis, etc.), with the investigator determining that the patients liver function would remain stable for ≥1 month based on clinical presentation;
• Participants who voluntarily sign the informed consent form and agree to cooperate in completing the trial according to the protocol.

Inclusion criteria

for participants with normal liver function (all 6 criteria must be met)：

• Adults aged 18 ~ 75 years (inclusive), regardless of gender(matched for age and gender with the hepatic impairment group);
• Body weight ≥ 45.0 kg (female) or ≥ 50.0 kg (male), body mass index (BMI) in the range of 19 ~ 32 kg/m2 (inclusive);
• Participants whose medical history, vital signs, physical examination, laboratory tests (hematology, blood biochemistry, urinalysis, coagulation function, infectious disease screening, and other relevant tests), Chest X-ray, abdominal color Doppler ultrasound, and other examination must be deemed suitable for participation in this study by the investigator;
• Participants and their partners must use effective contraception (e.g., condoms, inert intrauterine devices, etc.) from 2 weeks prior to screening until 6 months after the end of the study, unless they have already undergone permanent sterilization procedures, such as bilateral tubal ligation or vasectomy; furthermore, they must not donate sperm or eggs.
• Participants must have not taken any medications within 2 weeks prior to screening, or must have been on a stable medication regimen for at least 4 weeks for the treatment of other comorbidities;
• Participants who voluntarily sign the informed consent form and agree to cooperate in completing the trial according to the protocol.

Exclusion criteria

Participants meeting any of the following criteria will be excluded from this trial:

• Individuals with a history of allergies (allergic to two or more drugs, foods, or pollens);
• Individuals with major psychiatric disorders, renal disease, neurological disorders, or other systemic diseases that the investigator deems may affect trial results;
• Individuals with orthostatic hypotension (a decrease in systolic blood pressure of 20 mmHg or diastolic blood pressure of 10 mmHg upon standing compared to the supine position);
• Participants with a 12-lead ECG QTcF>470 ms, or those with abnormal ECG findings that the study physician determines may influence the study results, or those with a history of severe arrhythmias, arrhythmia-related syncope, use of a cardiac pacemaker, or other cardiac-related conditions. Conditions include but are not limited to: heart failure; non-sustained or sustained ventricular tachycardia; sick sinus syndrome; or a family history of sudden death;
• Smokers or heavy drinkers within 4 weeks prior to screening (consuming 14 units of alcohol per week: 1 unit = 285 mL of beer, 25 mL of spirits, or 150 mL of wine; smoking ≥5 cigarettes per day) or those with a history of substance or drug abuse within the past year;
• Individuals with a history of dysphagia or any gastrointestinal disease affecting drug absorption;
• Participants with CYP2D6 poor metabolizer;
• Individuals with a positive breathalyzer test for alcohol or a positive urine test for drug abuse during the screening period;
• Individuals who have donated or lost more than 200 mL of blood within 8 weeks prior to screening;
• Participants who have participated in other drug clinical trials within 3 months prior to screening (as determined by the date of administration);
• Individuals who habitually consumed excessive amounts of caffeinated beverages or foods within 4 weeks prior to screening. Examples include coffee, tea, chocolate, cola, and Red Bull (daily caffeine intake should not exceed 6 units).1 caffeine unit = 1 cup of coffee (177.4 mL) = 2 cans of cola (354.9 mL) = 1 cup of tea (354.9 mL) = 1/2 cup of energy drink = 85 g of chocolate;
• Participants who used strong or moderate inhibitors of liver enzymes (CYP2D6) within 4 weeks prior to screening;
• Individuals who have consumed dragon fruit, mango, pomelo, grapefruit, lime, star fruit, pomegranate, or foods or beverages prepared from these fruits within 7 days prior to screening;
• Pregnant or breastfeeding women, or female participants who test positive for pregnancy during the screening period;
• Individuals with estimated glomerular filtration rate (eGFR) < 75 mL/min/1.73 m²calculated using the 2021 CKD-EPI formula based on serum creatinine levels during the screening period;
• Participants with uncontrolled bacterial, viral, parasitic, or fungal infections requiring treatment at screening (excluding hepatitis B), or a history of severe active infection within 1 month prior to screening;
• Participants deemed by the investigator to be unsuitable for this clinical trial for other reasons.

Additional exclusion criteria for participants with hepatic impairment (exclusion if any one criterion is met):

• Participants with clinically significant abnormalities in infectious disease screening as determined by the investigator (e.g., patients with active viral hepatitis such as hepatitis B or C) ;
• Participants who have received albumin within 14 days prior to screening;
• Participants with alpha-fetoprotein (AFP) > 40 ng/mL; or hemoglobin (Hb) ≤ 70 g/L; or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 5 times the upper limit of normal (ULN); or total bilirubin ≥ 5 times the ULN; or platelet count ≤ 30 × 109/L;
• Patients with drug-induced liver injury; within 2 years of liver cancer surgery; history of liver transplantation; acute liver dysfunction due to any cause; patients with diseases affecting bile excretion, such as biliary cirrhosis, biliary obstruction, or cholestatic liver disease; patients with a history of portal-systemic shunt surgery, including transjugular intrahepatic portosystemic shunt (TIPS);
• Patients with a history of any serious disease other than the primary liver disease itself, or a medical history and/or clinically significant abnormal laboratory findings that the investigator believes may affect the trial results, including but not limited to a history of diseases of the circulatory, endocrine, nervous, digestive, or urinary systems, or of hematological, immunological, psychiatric, or metabolic disorders;
• Participants with severe complications of cirrhosis who also have any of the following conditions: active bleeding from ruptured esophageal or fundic varices; severe or advanced ascites or pleural effusion requiring paracentesis, drainage, and albumin supplementation; participants with hepatorenal syndrome; overt hepatic encephalopathy; liver failure; or other conditions deemed by the investigator to render the participant unsuitable for the study;

Additional exclusion criteria for participants with normal liver function (exclusion if any one criterion is met):

• Participants with a history of liver dysfunction, or physical examination and laboratory tests at screening indicating the presence or possible presence of liver dysfunction;
• Participants who have a positive result for hepatitis B surface antigen (HBsAg) or any hepatitis C virus antibody test.