Hepatic Impairment
Conditions
Brief summary
This study will investigate the pharmacokinetics, safety, and tolerability of DZD9008 in subjects with hepatic impairment compared to subjects with normal hepatic function
Interventions
DRUGDZD9008
A single oral dose of 200mg DZD9008
Sponsors
PPD Development, L.P.
Dizal Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. The subject is male or female 18 to 75 years of age, inclusive, at screening. 2. The subject has a BMI of 18.0 to 40.0 kg/m2, inclusive, at screening and check-in. 3. The subject has a minimum body weight of 50.0 kg, at screening and check-in. 4. The subject has a resting pulse rate of ≥ 40 and \< 100 beats per minute with no clinically significant deviation as judged by the investigator. 5. The subject agrees to comply with all protocol requirements. 6. The subject is able to provide written informed consent. Additional Inclusion Criteria for Healthy Subjects Only (Cohort 2) Only (7-11): 7. The subject has normal hepatic function. No known or suspected hepatic impairment based on liver function tests (e.g., ALT, AST, ALP, and bilirubin), albumin, and prothrombin time is defined as the following with a single repeat permitted to assess eligibility if needed, at screening and check-in: 1. ALT and AST ≤ ULN 2. Total bilirubin ≤ ULN (subjects with a history of Gilbert syndrome are eligible if they only have elevated total bilirubin) 3. ALP ≤ ULN 4. Albumin ≥ 3.6 g/dL 5. Prothrombin time ≤ ULN 8. The subject has a resting blood pressure of 90 to 145 mmHg (systolic) and 40 to 95 mmHg (diastolic), at screening and check-in. 9. The subject has a QTcF of ≤ 450 msec, at screening and check-in. 10. The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings. 11. Each subject with normal hepatic function (Cohort 2) must individually match a subject with impaired hepatic function (Cohort 1) by age (± 10 years), body weight (± 10 kg), and sex (similar distribution of males and females). Additional Inclusion Criteria for Subjects with Hepatic Impairment (Cohort 1) Only (12-18): 12. The subject satisfies the Class B of the Child-Pugh classification (no albumin use within 14 days). Six out of 10 subjects also meet NCI ODWG Group C criteria. 13. The subject has a diagnosis of hepatic dysfunction due to hepatocellular disease (and not secondary to any acute ongoing hepatocellular process), with features of cirrhosis due to any etiology, except for DILI, which is confirmed by at least one of the following criteria: 1. histologically by prior liver biopsy showing cirrhosis 2. clinically by physical examination, laboratory data, liver imaging, or endoscopic findings 14. The subject has following clinical laboratory values, at screening and check-in: 1. ALT and AST ≤ 5 × ULN 2. Total bilirubin ≤ 3 × ULN 3. ANC ≥ 1.5 × 109/L 4. Platelet count ≥ 30 × 109/L 5. Hemoglobin ≥ 90 g/L 15. The subject has chronic (more than 6 months) and stable hepatic impairment (ie, no acute episodes of illness within 30 days before screening due to deterioration of hepatic function) as assessed by the NCI-ODWG criteria (Group C) or a Child-Pugh classification score of moderate (7 to 9 points). 16. The subject has a resting blood pressure of 90 to 155 mmHg (systolic) and 50 to 100 mmHg (diastolic), at screening and check-in. 17. The subject has a QTcF of ≤ 470 msec, at screening and check-in. 18. The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings, except for findings that, as judged by the investigator, are consistent with the subject's hepatic impairment or other stable concomitant medical conditions.
Exclusion criteria
1. The subject has a history or clinical manifestations of a significant neurological, renal, cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric disease that would preclude study participation, as judged by the investigator. 2. The subject has any surgical or medical condition that may alter the absorption, distribution, metabolism, or excretion of drugs (e.g., gastrectomy). 3. The subject has a history of cancer (malignancy) with the following exceptions: 1. adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix, or 2. other malignancies which have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study 4. The subject has a history of being immunocompromised or has a positive test result for HIV types 1 or 2 antibodies at screening. 5. The subject has an acute or chronic infection requiring treatment with oral antibiotics (except, rifaximin for the treatment of hepatic encephalopathy), antivirals, antiparasitic, antiprotozoals, or antifungals within 4 weeks prior to Day 1 or superficial skin infection within 1 week prior to Day 1. 6. The subject has a history of risk factors for Torsades de Pointes (e.g., heart failure/cardiomyopathy or family history of long QT syndrome), has clinically significant hypokalemia or hypomagnesemia, and is taking concomitant medications that prolong the QT/QTc interval. 7. The subject has uncontrolled hypertension despite optimal medical management. 8. The subject had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study drug administration. 9. The subject tests positive for breath alcohol test at screening and on check-in (Day 1). 10. The subject is unable or unwilling to restrict smoking to 5 cigarettes or less per day. 11. The subject is involved in strenuous activity or contact sports within 24 hours of the first dose of study drug or during the study. 12. The subject has donated blood (excluding plasma donation) of ≥ 500 mL within 60 days before the first dose of study drug. 13. The subject has poor peripheral venous access. 14. The subject should not be any of the following: 1. investigator staff member or their family members 2. site staff member otherwise supervised by the investigator, or employees, including their family members, directly involved in the conduct of the study 15. The subject has a history of relevant drug and/or food allergies (ie, allergy to DZD9008 or any excipients, or any significant food allergy). 16. The subject has received DZD9008 or any other investigational drug in another investigational study within 30 days of dosing. 17. The subject is enrolled in another clinical study or has used any investigational drug or device within 4 weeks (or 5 times the half-life of the pervious drug \[if known\], whichever is longer), prior to dosing with study drug. The window will be derived from the date of the last dose of study drug in the previous study. 18. The subject has used a strong or moderate inhibitor or inducer of CYP3A4 and/or P gp including St. John's Wort, within 14 days and 28 days, respectively, prior to dosing and until the completion of the last PK sample collection unless it is deemed acceptable following consultation with Dizal Pharma's medical monitor and the investigator. 19. The subject has used PPIs within 5 days prior to dosing until 24 hours after dosing. Use of H2-antagonists and antacids within 12 hours prior to dosing until 12 hours after dosing unless it is deemed acceptable following consultation with Dizal Pharma's medical monitor and the investigator. 20. In the opinion of the investigator, the subject is not suitable for entry into the study. Additional
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area under the plasma concentration-curve from time zero to last quantifiable concentration (AUClast) | Day 1 to day 14 |
| Maximum observed plasma (peak) drug concentration [Cmax] | Day 1 to day 14 |
| Area under plasma concentration time curve from zero to infinity (AUCinf) | Day 1 to day 14 |
Secondary
| Measure | Time frame |
|---|---|
| Terminal phase half-life (t1/2), | Day 1 to day 14 |
| Fraction unbound (Fu) | Day 1 to day 14 |
| Unbound area under plasma concentration time curve from zero to infinity (AUC0-inf, u) | Day 1 to day 14 |
| Unbound area under the plasma concentration-curve from time zero to last quantifiable concentration (AUC0-last, u) | Day 1 to day 14 |
| Unbound maximum observed plasma (peak) drug concentration (Cmax, u) | Day 1 to day 14 |
| Unbound apparent total body clearance (CLu/F) | Day 1 to day 14 |
| Time to maximum observed plasma concentration (Tmax) | Day 1 to day 14 |
| Adverse events | Day 1 to day 14 |
| Clinical laboratory test results: hematology, coagulation, serum chemistry, urinalysis | Day 1 to day 14 |
| 12-lead ECG results: tracings, rhythm, RR interval, PR interval, QRS width, QT interval, and QTcF | Day 1 to day 14 |
| Vital sign measurements: systolic and diastolic blood pressure, pulse rate, respiratory rate and body temperature | Day 1 to day 14 |
| Physical examination findings: assessment of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, lymph nodes, and musculoskeletal system/extremities | Day 1 to day 14 |
| Unbound apparent volume of distribution (Vz,u/F) | Day 1 to day 14 |
| Apparent total body clearance (CL/F) | Day 1 to day 14 |
| Area under plasma concentration time curve from zero to infinity (AUCinf) | Day 1 to day 14 |
Countries
United States
Outcome results
None listed