A Phase I, Single-dose, Open-label, Parallel-group Study to Assess the Pharmacokinetics, Safety, and Tolerability of FIA586 in Participants With Mild and Moderate Hepatic Impairment Compared to Matched Healthy Participants
Overview
- Phase
- Phase 1
- Intervention
- FIA586
- Conditions
- Hepatic Impairment
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 54
- Locations
- 1
- Primary Endpoint
- Area Under Plasma Concentration-time Curve from time zero to the last measurable concentration sampling time (AUClast) for FIA586
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This is a Phase I study designed to characterize the pharmacokinetics (PK), safety, and tolerability of a single oral dose of FIA586 in participants with mild and moderate hepatic impairment (HI) compared to matched healthy participants.The information obtained in this study will help to determine whether dosage adjustment for FIA586 is necessary in patients with advanced liver fibrosis who have mild to moderate HI.
Detailed Description
This is a Phase I, single-dose, open-label, parallel-group study in participants with mild (Child-Pugh A; n=8-10) and moderate (Child-Pugh B; n=8-10) hepatic impairment (HI) and matched healthy participants with normal hepatic function (n=8-20). The study is comprised of an up to 28-day screening period (Days -28 to 2), a baseline evaluation (Day -1) prior to dosing on Day 1, and a treatment period of 6 days (Days 1-6). Participants will remain domiciled up to Day 6 after the Study Completion procedures have been completed. On Day 1, participants will be given a single dose of FIA586 following an overnight fast. PK (plasma and urine) and biomarker samples will be taken prior to dosing of study treatment and up to 120 hours (Day 6) post- dose. On Day 6, after the last PK sample has been taken, Study Completion assessments will be performed, and the participant will be discharged, provided there are no safety or tolerability concerns as judged by the investigator. All participants will have a post-study safety contact conducted approximately 30 days after administration of study treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •All Participants:
- •Male and non-childbearing potential female participants 18 to 70 years of age (inclusive) at Screening.
- •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 at Screening.
- •Must be a non-smoker or agree to smoke no more than 5 cigarettes (or equivalent) per day, and maintain the same smoking status from Screening until the Study Completion (Day -28 to Day 6).
- •Healthy participants (Group 1)
- •Must be in good health as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests at Screening.
- •Each participant must match in age (±10 years), gender, weight (±15%), and smoking status (smoker or non-smoker) to an individual participant in at least one HI group but not to more than 1 participant in the same HI group.
- •Participants with mild and moderate HI (Groups 2 and 3)
- •Must satisfy the criteria for HI as evidenced by a Child-Pugh class of A or B at Screening:
- •Class A; Mild; Child-Pugh score 5-6
Exclusion Criteria
- •All participants:
- •Use of other investigational drugs within the last 30 days or 5 half-lives prior to dosing of study treatment, whichever is longer.
- •Known history of, or current clinically significant arrhythmias. Have clinically significant ECG abnormality or history of long-QT syndrome.
- •Myocardial infarction \< 5 years prior to Screening.
- •Recent (within the last 3 years of Screening) or recurrent history of autonomic dysfunction (e.g. recurrent episodes of fainting or palpitations).
- •History of immunodeficiency diseases or have a positive HIV test result at Screening.
- •History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 3 years of Screening, regardless of whether there is evidence of local recurrence or metastases.
- •Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (apart from cholecystectomy), or which may jeopardize the participants in case of participation in the study. The investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence of any of the following:
- •Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding within 3 months prior to Screening.
- •Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection.
Arms & Interventions
Group 1: Healthy participants with normal hepatic function
Each participant will receive a single dose of FIA586
Intervention: FIA586
Group 2: Participants with mild hepatic impairment
Each participant will receive a single dose of FIA586
Intervention: FIA586
Group 3: Participants with moderate hepatic impairment
Each participant will receive a single dose of FIA586
Intervention: FIA586
Outcomes
Primary Outcomes
Area Under Plasma Concentration-time Curve from time zero to the last measurable concentration sampling time (AUClast) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to measure AUClast at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. AUClast will be determined using non-compartmental methods.
Area Under Plasma Concentration-time Curve from time 0 to 48 hours (AUC0-48h) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours and 48 hours
Blood samples will be collected to measure AUC0-48h at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. AUC0-48h will be determined using non-compartmental methods.
Apparent volume of distribution during terminal elimination phase (Vz/F) of FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to estimate Vz/F at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL.
Time to Reach Maximum Blood Concentrations (Tmax) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to measure Tmax at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. Tmax will be determined using non-compartmental methods.
Maximum Observed Blood Concentrations (Cmax) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to measure Cmax at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. Cmax will be determined using non-compartmental methods.
Area Under Plasma Concentration-time Curve from Time Zero Extrapolated to Infinity (AUC[0-inf]) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to measure AUC(0-t) at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. AUC\[0-inf\] will be determined using non-compartmental methods
Terminal Elimination Half-life (T1/2) for FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to measure T1/2 at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL. T1/2 will be determined using non-compartmental methods.
Apparent Clearance (CL/F) of FIA586
Time Frame: pre-dose, 0.25 hours, 0.5 hours, 1 hour, 1,5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 92 hours and 120 hours
Blood samples will be collected to estimate CL/F at indicated time-points. Pharmacokinetic (PK) parameters will be calculated based on FIA586 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC MS/MS) method with a lower limit of quantification of 20 ng/mL.