Hepatic Impairment
Conditions
Keywords
hepatic impairment,, INC280,, Oral cMET Inhibitor,, Non-Cancer
Brief summary
This is a phase I, multi-center, open-label, single oral dose, parallel group study to evaluate the pharmacokinetics and safety of INC280 in non-cancer subjects with impaired hepatic function and non-cancer subjects with normal hepatic function.The study population will be healthy male and postmenopausal or sterile female subjects who meet all of the inclusion and none of the exclusion criteria. Subjects will be assigned to groups according to their hepatic function: normal (Group 1), mild (Group 2), moderate (Group 3), and severe (Group 4) impairment. This study consists of a two-staged design with interim analysis. In Stage 1, subjects in Groups 1, 2 and 3 will be enrolled. Upon completion of Stage 1, an interim analysis will be conducted. Depending on the results of the analysis, either the study will conclude with no further enrollment or Stage 2 will commence with enrollment of Group 4. A minimum of 6 evaluable subjects per group will be enrolled.Once enrolled in the study, participants will be confined to the facility for 4 days, given a single dose of INC280 and monitored for pharmacokinetic and safety assessments.
Interventions
DRUGINC280
Single 200 mg dose INC280
Sponsors
Novartis 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
(all groups): * Female subjects must be postmenopausal or sterile * Good health, as determined by absence of clinically significant findings in medical history, physical examination, vital signs, and ECGs, unless it is consistent with known clinical disease for hepatic impairment subjects * Adequate organ function and normal laboratory tests, unless it is consistent with known clinical disease for hepatic impairment subjects * Body Mass Index (BMI) of 18- 36 kg/m2, with body weight ≥ 50 kg Inclusion Criteria (hepatic impairment groups): * Confirmed liver disease * Stable comorbidities are allowed as long as generally considered healthy * Subjects with hepatic impairment must meet the following laboratory values: * Aspartate transaminase (AST) ≤ 5 x ULN * Alanine transaminase (ALT) ≤ 5 x ULN * Total bilirubin ≤ 3 x ULN (≤ 5 x XULN for subjects with severe hepatic impairment \[group 4\]) * Calculated creatinine clearance (using Cockcroft-Gault formula) ≥ 45 mL/min * Platelets \> 50 x 10\^9/L. Subjects with severe hepatic impairment can be enrolled if platelet count \> 40 x 10\^9/L
Exclusion criteria
(all groups): * History or presence of clinically significant ECG abnormalities or clinically significant cardiovascular disease * Immunocompromised subjects, including HIV * Use of drugs known to affect CYP3A4 * Use of QT-prolonging drugs * Use of any other drugs, unless they are required to treat the hepatic impairment subject's disease * Use of proton pump inhibitors (PPI) medications within 7 days prior to dosing and during the current study until last day of confinement
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUClast of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| AUCinf of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| Cmax of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| Tmax of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| T1/2 of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| CL/F of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
| Vz/F of INC280 | Up to 72 hours post-dose | INC280 pharmacokinetic parameters |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events based on the CTCAE v4.03 grade (severity) and frequency, and other safety data (e.g., ECG, laboratory results) | Up to 30 days | Safety |
| Unbound fraction and Vz/F based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and AUClast based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and AUCinf based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and Cmax based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and Tmax based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and T1/2 based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
| Unbound fraction and CL/F based on unbound concentration in plasma | 3 hours post-dose | To assess the plasma protein binding of INC280 |
Countries
United States
Outcome results
None listed