An Open-Label, Phase 1 Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics of Olverembatinib
Overview
- Phase
- Phase 1
- Intervention
- Olverembatinib 20mg
- Conditions
- Not specified
- Sponsor
- Ascentage Pharma Group Inc.
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Apparent Clearance (CL/F)
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This is a non-randomized, open-label, parallel, single-dose study to evaluate the pharmacokinetic profile of olverembatinib in participants with normal or impaired liver function.
Detailed Description
To evaluate the PK characteristics of olverembatinib in participants with mild hepatic impairment (Child-Pugh Class A), moderate hepatic impairment (Child-Pugh Class B), severe hepatic impairment (Child-Pugh Class C) and sex, age, and body weight-matched healthy participants with normal hepatic function, so as to provide a scientific basis for the appropriate dose and/or dosing interval adjustment in participants with hepatic impairment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The participant voluntarily joins the study, signs the Informed Consent Form, and demonstrates good compliance.
- •Body Mass Index (BMI) between 18 and 30 kg/m² (inclusive), with male weight ≥ 50 kg and female weight ≥ 45 kg.
- •The investigator judges the participant suitable to participate in this study based on physical examination, vital signs, laboratory tests, and 12-lead electrocardiogram (ECG) examination.
- •Female participants of childbearing potential must agree to use effective contraception during the study and for 3 months after the study ends; must have a negative serum pregnancy test within 7 days prior to study enrollment; and must not be breastfeeding. Male participants must agree to use effective contraception during the study and for 3 months after the study ends.
- •Additional Criteria for Participants with hepatic impairment Only:
- •1\. Chronic hepatic impairment due to viral hepatitis, alcoholic liver disease, autoimmune hepatitis, or other causes.
- •2\. Hepatic impairment classified as Child-Pugh Class A, B, or C.
- •Coagulation function: INR ≤ 2.5 without intervention with procoagulant drugs (after a 2-week washout period). Hematology: Neutrophils ≥ 1.0 × 10⁹/L, Hemoglobin ≥ 70 g/L, Platelets ≥ 30 × 10⁹/L. Liver function: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 5 times the Upper Limit of Normal (ULN); Total Bilirubin ≤ 5 × ULN.
- •4\. Stable treatment for hepatic impairment, complications, and other concomitant diseases prior to study drug administration, with no need for dosage adjustment. Treatment for hepatic impairment must have been stable for at least 4 weeks.
Exclusion Criteria
- •Drug-induced liver injury.
- •Any of the following conditions: history of liver transplantation; presence of acute or worsening liver injury due to any cause; liver failure; concurrent Grade 3/4 hepatic encephalopathy; active hepatocellular carcinoma lesions; severe esophageal or gastric varices or history of rupture and bleeding; severe/late-stage ascites or pleural effusion requiring paracentesis/thoracentesis and albumin supplementation; hepatorenal syndrome; or any other condition deemed by the investigator as unsuitable for study participation.
- •History of cholestasis, biliary tract infection, or other diseases affecting bile excretion within 3 months prior to screening.
- •Esophageal or gastric variceal bleeding due to portal hypertension within 3 months prior to screening, or history of portosystemic shunt surgery (including Transjugular Intrahepatic Portosystemic Shunt - TIPS) within 6 months prior to screening.
- •History of significant allergy or intolerance to any drug, food, or other substance.
- •History of any clinically significant disease in the neurological, cardiovascular, digestive, respiratory, urinary, endocrine, hematological, immune systems, or any other disease or condition that the investigator believes may affect the trial results.
- •History of surgery that may affect drug absorption, distribution, metabolism, or excretion, or plans for surgery or other reasons requiring hospitalization during the expected study period.
- •Uncontrolled bacterial, viral, parasitic, or fungal infection requiring treatment at the time of screening (except Hepatitis B), or history of severe active infection within 1 month prior to screening.
- •Positive Human Immunodeficiency Virus (HIV) antigen/antibody test at screening. For participants with normal hepatic function: Positive Treponema pallidum antibody. For hepatically impaired participants: Active syphilis.
- •Use of systemic medications with known potential hepatotoxicity for 7 consecutive days or more within 14 days prior to study drug administration.
Arms & Interventions
Group 6: 6-8 participants with normal hepatic function matched to Group 5
Intervention: Olverembatinib 20mg
Group 1: 6-8 participants with mild hepatic impairment.
Intervention: Olverembatinib 20mg
Group 2: 6-8 participants with normal hepatic function matched to Group 1
Intervention: Olverembatinib 20mg
Group 3: 6-8 participants with moderate hepatic impairment
Intervention: Olverembatinib 20mg
Group 4: 6-8 participants with normal hepatic function matched to Group 3
Intervention: Olverembatinib 20mg
Group 5: 6-8 participants with severe hepatic impairment
Intervention: Olverembatinib 20mg
Outcomes
Primary Outcomes
Apparent Clearance (CL/F)
Time Frame: Day 1 to Day 9
The CL/F of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated.
Maximum observed plasma concentration C(max)
Time Frame: Day 1 to Day 9
The C(max) of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared.
Time to C(max) [ t(max) ]
Time Frame: Day 1 to Day 9
The t(max) of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated.
Apparent terminal elimination half-life (t½)
Time Frame: Day 1 to Day 9
The t½ of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated.
Area under the concentration-time curve from time zero to last time of quantifiable concentration [AUC(last)]
Time Frame: Day 1 to Day 9
The AUC(last) of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared.
Area under the concentration-time curve from time zero to 192h AUC(0-192h)
Time Frame: Day 1 to Day 9
The AUC(0-192h) of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared.
Apparent Volume of distribution (Vz/F)
Time Frame: Day 1 to Day 9
The Vz/F of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated.
Unbound Fraction (fu)
Time Frame: Day 1 to Day 9
The unbound fraction (fu) of a single dose of olverembatinib in participants with impaired hepatic function and controls with normal hepatic function will be evaluated.
Secondary Outcomes
- Safety evaluation endpoints(Day1-Day21)