Hepatic Failure
Conditions
Keywords
Hepatic impairment, Child-Pugh classification, Icenticaftor, QBW251
Brief summary
The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic pharmacokinetics, safety, and tolerability of icenticaftor in participants with varying degrees of hepatic impairment.
Detailed description
This is a Phase 1, multi-center study with parallel groups. The study employs a single-dose, open-label design in subjects with mild, moderate, or severe hepatic impairment along with matched healthy control subjects with normal hepatic function. Subjects with normal hepatic function will be matched with subjects with hepatic impairment for gender, age (± 10 years), body weight (± 15%), and smoking status (smoker or non-smoker). Up to a total of 48 participants will be enrolled in this study (approximately 8 in each mild \[Child-Pugh A\], moderate \[Child-Pugh B\], severe hepatic impairment \[Child-Pugh C\] groups), and up to 24 healthy control subjects). Each participant will receive a single oral dose of 300 mg of icenticaftor (QBW251) on Day 1 under fasting conditions. The study is comprised of an up to 28-day screening period (Days -28 to -1), a baseline evaluation (Day -1) prior to treatment on Day 1, and a follow-up period of 7 days for pharmacokinetics (PK) sample collection (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose). A safety follow-up contact will be done 30 days after administration of the study drug. The primary purpose of this study is to evaluate the effect of hepatic impairment on the systemic PK, safety, and tolerability of icenticaftor in participants with varying degrees of hepatic impairment.
Interventions
DRUGIcenticaftor
Single oral dose of 300 mg of icenticaftor (QBW251)
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 Participants: Inclusion Criteria: * Male and non-child bearing potential female participants, 18 to 75 years of age (inclusive) at Screening. * Participants must weigh at least 50.0 kg and must have a body mass index (BMI) within the range of 18.0 to 38.0 kg/m2, inclusive, at Screening. * Must be a non-smoker or agree to smoke no more than 5 cigarettes (or equivalent) per day from Screening until the End of Study. Participants must maintain the same smoking status throughout the study (i.e. smoker or non smoker).
Exclusion criteria
* Use of other investigational drugs within 5 half-lives prior to dosing of study treatment, or within 30 days, whichever is longer; or longer if required by local regulations. * Are taking medications prohibited to be taken with the study treatment * Known history of, or current clinically significant arrhythmias. Have clinically significant ECG abnormality or history of long-QT syndrome or whose QT interval corrected by Fridericia's formula (QTcF) is prolonged (\> 480 msec) at Screening. Participants having myocardial infarction ≥ 5 years ago are eligible to participate. * Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection. Healthy Participants: * Each participant must match in age (± 10 years), gender, weight (± 15%), and smoking status to participants in Group 2, 3, or 4. * Seated vital signs must be within the following ranges at Screening and Baseline: * Body temperature, 35.0 to 37.5°C, inclusive. * Systolic blood pressure, 89 to 149 mmHg, inclusive. * Diastolic blood pressure, 50 to 89 mmHg, inclusive. * Pulse rate, 40 to 90 bpm, inclusive. * Participants must be in good health as determined by medical history, physical examination, ECG, and clinical laboratory tests at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Elimination half-life (T1/2) of icenticaftor after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | T1/2 of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). Regression analysis of the terminal plasma elimination phase will be used for T1/2 calculation. |
| Area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of icenticaftor after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | AUClast of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). The linear trapezoidal rule will be used for AUClast calculation. |
| Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of icenticaftor after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | AUCinf of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). The linear trapezoidal rule will be used for AUCinf calculation. |
| Time to reach maximum icenticaftor plasma concentration (Tmax) after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor plasma concentrations will be determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Tmax of icenticaftor will be determined with Phoenix WinNonlin (Version 6.4 or higher). |
| Apparent plasma clearance (CL/F) of icenticaftor after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | CL/F of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). |
| Apparent volume of distribution during terminal phase (Vz/F) of icenticaftor after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Vz/F of icenticaftor will be determined using non-compartment methods with Phoenix WinNonlin (Version 6.4 or higher). |
| Maximum observed icenticaftor plasma concentration (Cmax) after single oral dose | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor plasma concentrations will be determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of icenticaftor will be determined with Phoenix WinNonlin (Version 6.4 or higher). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of unbound icenticaftor (Cmax,u) | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor Cmax,u will be calculated as Cmax\*fu. |
| AUClast of unbound icenticaftor (AUClast,u) | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor AUClast,u will be calculated as AUClast\*fu. |
| AUCinf of unbound icenticaftor (AUCinf,u) | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor AUCinf,u will be calculated as AUCinf\*fu. |
| CL/F of unbound icenticaftor (CL/F,u) | pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose | Icenticaftor CL/F,u will be calculated as CL/F/fu. |
| Plasma protein binding free fraction (unbound fraction [fu]) of icenticaftor | 3 hours post-dose | The free fraction in plasma fu of icenticaftor will be evaluated at 3 hours post-dose using equilibrium dialysis method. |
Countries
United States
Outcome results
None listed