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

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

Use these resources to provide understandable information about this study to patients, families, and health care providers:This study is a multi-center, non-randomized, open-label, parallel-group, multiple-dose Phase I clinical trial evaluating the pharmacokinetic characteristics of ammoxetine hydrochloride enteric-coated tablets in participants with mild hepatic impairment (Child-Pugh Class A), moderate hepatic impairment (Child-Pugh Class B), and participants with normal liver function who are matched for age, weight, and gender. Participants in all groups receive 20 mg of ammoxetine hydrochloride enteric-coated tablets daily at 1 hour after meals, from day 1 to day 6. Blood samples for pharmacokinetic (PK) analysis, and safety parameters are collected before and after dosing according to the trial protocol.

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Inclusion Criteria:

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

1. Adults aged 18 ~ 75 years (inclusive), regardless of gender
2. Body weight ≥ 45.0 kg (female) or ≥ 50.0 kg (male), body mass index (BMI) in the range of 19 ~ 32 kg/m2 (inclusive);
3. 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;
4. 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.
5. 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;
6. 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;
7. 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)：

1. Adults aged 18 ~ 75 years (inclusive), regardless of gender(matched for age and gender with the hepatic impairment group);
2. Body weight ≥ 45.0 kg (female) or ≥ 50.0 kg (male), body mass index (BMI) in the range of 19 ~ 32 kg/m2 (inclusive);
3. 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;
4. 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.
5. 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;
6. 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:

1. Individuals with a history of allergies (allergic to two or more drugs, foods, or pollens);

2. Individuals with major psychiatric disorders, renal disease, neurological disorders, or other systemic diseases that the investigator deems may affect trial results;

3. 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);

4. 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;

5. 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;

6. Individuals with a history of dysphagia or any gastrointestinal disease affecting drug absorption;

7. Participants with CYP2D6 poor metabolizer;

8. Individuals with a positive breathalyzer test for alcohol or a positive urine test for drug abuse during the screening period;

9. Individuals who have donated or lost more than 200 mL of blood within 8 weeks prior to screening;

10. Participants who have participated in other drug clinical trials within 3 months prior to screening (as determined by the date of administration);

11. 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;

12. Participants who used strong or moderate inhibitors of liver enzymes (CYP2D6) within 4 weeks prior to screening;

13. 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;

14. Pregnant or breastfeeding women, or female participants who test positive for pregnancy during the screening period;

15. 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;

16. 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;

17. 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):

18. 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) ;

19. Participants who have received albumin within 14 days prior to screening;

20. 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;

21. 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);

22. 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;

23. 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):

24. Participants with a history of liver dysfunction, or physical examination and laboratory tests at screening indicating the presence or possible presence of liver dysfunction;

25. Participants who have a positive result for hepatitis B surface antigen (HBsAg) or any hepatitis C virus antibody test.