A Clinical Study to Evaluate the Pharmacokinetics and Safety of Anecatibin Fumarate Capsules in Subjects With Impaired Liver Function Versus Normal Liver Function

Official title

Phase I Clinical Study to Evaluate the Pharmacokinetics and Safety of Anecatibin Fumarate Capsules in Subjects With Impaired Liver Function Versus Normal Liver Function

Overview

Evaluation of the Pharmacokinetics and Safety of Anecatibin Fumarate Capsules in Subjects with Impaired Liver Function versus Normal Liver Function

Interventions

• Drug Anecatibin Fumarate Capsules
  Anecatibin fumarate capsule is a prodrug that can be rapidly hydrolyzed into crizotinib in vivo to exert pharmacodynamic effects. Crizotinib is a tyrosine kinase receptor inhibitor, including Anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor Hepatocyte Growth Factor Receptor(HGFR, c-Met), ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1, c-cos), and Recepteur d'Origine Nantais (RON).

Primary outcome measures

• To determine the Cmax [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]
• To determine the Area Under the Curve (AUC) 0-t [Time frame: The period extends from the date of the first dose to the completion of the end of treatment (EOT) visit, totaling 5 days]
• To determine the AUC 0-∞ [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]

Secondary outcome measures (5)

• Tmax of TQ-B3101 and its benzyloxy pyridine metabolite [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]
• t1/2 of TQ-B3101 and its benzyloxy pyridine metabolite [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]
• Vz/F of TQ-B3101 and its benzyloxy pyridine metabolite [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]
• Apparent Clearance (CLz/F) of TQ-B3101 and its benzyloxy pyridine metabolite [Time frame: The period extends from the date of the first dose to the completion of the EOT visit, totaling 5 days]
• Numbers of subjects with adverse events [Time frame: The period extends from the first dose date to the completion of the safety follow-up, not to exceed 90 days]

Eligibility criteria

Inclusion criteria

All subjects must meet all of the following inclusion criteria:

• Provide signed informed consent prior to trial participation and have a full understanding of the trial content, procedures, and potential adverse reactions;
• Be male or female subjects aged 18 to 65 years (inclusive);
• Weigh at least 50 kg for males and at least 45 kg for females. Body Mass Index (BMI = weight (kg) / height² (m²)) within the range of 18 to 30 kg/m² (inclusive of boundary values);
• Subjects and their partners agree to voluntarily adopt effective contraceptive measures from screening until 6 months after the last dose;
• Subjects are able to communicate well with the investigators and can complete the study according to the study protocol.

Subjects with normal liver function must also meet the following inclusion criteria:

• Negative test results for Hepatitis B surface antigen and Hepatitis C antibody;
• Normal liver function test results or abnormal results without clinical significance;
• Matched with the hepatic impairment group in terms of male-to-female ratio (±1 subject per gender), mean age (±10 years), and mean body weight (±10 kg).

Subjects with hepatic impairment must meet the following inclusion criteria:

• Have a history of or be diagnosed at screening with primary liver disease, including but not limited to: Hepatitis B, Hepatitis C, non-alcoholic fatty liver disease, alcoholic liver disease, etc.;
• Hepatic impairment is caused by a previous primary liver disease (diagnosed at least 2 weeks prior to screening; excluding oncology patients) and is classified as Child-Pugh Class A or B;
• Liver function is stable within 2 weeks prior to taking the study drug, as determined by the investigator;
• No medication for liver disease within 4 weeks prior to screening, or on a stable medication regimen for existing underlying conditions.

Exclusion criteria

All subjects who meet any of the following exclusion criteria are not eligible for enrollment:

• Suffering from primary diseases of major organs, including but not limited to gastrointestinal, respiratory, renal, neurological, hematological, endocrine, oncological, immune, psychiatric, or cardiovascular diseases, as determined by the Investigator to be unsuitable for participation in this trial (except for hepatic impairment patients regarding their primary liver disease and complications of hepatic impairment);
• Physical examination, vital signs, or clinical laboratory tests (hematology, blood biochemistry, urinalysis, coagulation function) show abnormalities of clinical significance, as determined by the Investigator to be unsuitable for participation in this trial (except for hepatic impairment patients regarding their primary liver disease and complications of hepatic impairment);
• Participated in any drug clinical trial and used any investigational drug within 3 months prior to screening;
• Tested positive for HIV or syphilis screening;
• Subjects with conditions that may affect the absorption, distribution, metabolism, or excretion of the study drug (e.g., inability to swallow) or who have undergone gastrointestinal resection that may affect drug absorption, distribution, metabolism, or excretion;
• Electrocardiogram (ECG) abnormalities of clinical significance (e.g., tachycardia/bradycardia requiring medication, second- or third-degree atrioventricular block, or other abnormalities deemed clinically significant and unsuitable for participation by the Investigator);
• Used any CYP3A4 inhibitors (e.g., macrolide antibiotics such as clarithromycin, triazole antifungals such as itraconazole, and HIV protease inhibitors such as lopinavir) or CYP3A4 inducers (e.g., rifampicin, carbamazepine, and phenytoin) within 4 weeks prior to screening;
• Used any prescription drugs, over-the-counter medications, herbal medicines, or dietary supplements (e.g., vitamins, calcium supplements) within 2 weeks prior to screening, except for medications used by hepatic impairment patients to treat hepatic impairment and its complications;
• Known allergy to any component of TQ-B3101 capsules, or having an allergic constitution (including a history of drug allergy, prone to rashes, eczema, urticaria, asthma, etc.);
• Smoked an average of more than 5 cigarettes per day within 3 months prior to screening;
• Has a history of drug abuse within 3 months prior to screening, or tested positive for urine drug screening;
• Alcoholic liver disease patients have a history of alcoholism within 12 months prior to screening; other subjects have a history of alcoholism within 3 months prior to screening (average daily alcohol consumption > 2 units \[1 unit = 360 mL beer or 45 mL 40% spirits or 150 mL wine\]);
• Donated blood or plasma, lost ≥ 200 mL of blood, or undergone plasmapheresis within 4 weeks prior to screening;
• Consumed any food or beverage containing alcohol (or tested positive for alcohol breath test 1 day before dosing; alcoholic liver disease subjects consumed any alcohol-containing substances 2 weeks before dosing), grapefruit juice/pomelo juice, coffee, tea, cola, or chocolate within 1 week before dosing;
• Creatinine clearance (CLcr) < 60 mL/min (calculated by the Cockcroft-Gault formula);
• Female subjects who are lactating or test positive for pregnancy during screening or the trial period;
• Deemed by the Investigator to have any factors making them unsuitable for participation in this trial.

Subjects with hepatic impairment must also meet the following additional exclusion criteria:

• History of liver transplantation;
• Experienced hepatic encephalopathy within 30 days prior to screening;
• Used any medication that may cause acute hepatotoxicity (e.g., halothane and methotrexate) within 3 months prior to screening;
• Suffered from drug- or virus-induced acute hepatitis within 2 months prior to screening;
• Experienced a rapid deterioration or Alanine Aminotransferase/Aspartate Aminotransferase (ALT/AST) elevation > 3 times the upper limit of normal within 2 weeks prior to dosing, as judged by the Investigator;
• Experienced worsening of hepatic encephalopathy within 30 days prior to dosing;
• Suffering from diseases affecting bile excretion, such as biliary cirrhosis, hepatic/biliary obstruction, or cholestatic liver disease;
• Patients with liver failure or complications deemed unsuitable by the Investigator, such as hepatic encephalopathy, hepatocellular carcinoma, esophageal-gastric variceal bleeding within 3 months, severe portal hypertension, or history of portosystemic shunt surgery;
• As judged by the Investigator, having concomitant medications that may potentially affect the evaluation of the pharmacokinetic characteristics of TQ-B3101 and its metabolites.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• Xiamen Traditional Chinese Medicine Hospital — Xiamen
• Zhengzhou Sixth People's Hospital — Zhengzhou
• Qingdao University Affiliated Hospital — Qingdao

Identifiers

NCT: NCT07538973 · TQ-B3101-I-05

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗