The Effect of Hepatic Impairment on The Pharmacokinetics of Seladelpar: An Open-Label Study Following Oral Dosing of Seladelpar to Subjects With Primary Biliary Cholangitis (PBC) and Hepatic Impairment
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 40
- 主要终点
- Evaluate maximum concentration (Cmax) of seladelpar and metabolites
研究概览
简要总结
The Effect of Hepatic Impairment on The Pharmacokinetics of Seladelpar: An Open-Label Study Following Oral Dosing of Seladelpar to Participants with Primary Biliary Cholangitis (PBC) and Hepatic Impairment (HI)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females between 18 and 80 years of age (inclusive) who are able to comprehend instructions and follow the study procedures and are willing to sign an Informed Consent Form (ICF)
- •Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomized since at least 6 months) must be willing to use the contraceptive methods throughout the study and for 30 days after study drug administration.
- •For at least 90 days after study drug administration, non-vasectomized males must not donate sperm, be willing to use contraception with childbearing potential partners and any male participant with a pregnant partner must use a condom.
- •Willing to abstain from consuming grapefruit, pomelo, star fruit, or Seville orange containing products from 7 days prior to dose of study medication through day of discharge.
- •Confirmed diagnosis of PBC with evidence of cirrhosis and Child-Pugh classification of CP-A, CP-A + PHT, CP-B or CP-C
- •Screening laboratory parameters:
- •Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 10 × upper Limit of normal (ULN)
- •Total bilirubin ≤ 5 × ULN
- •Ursodeoxycholic acid (UDCA) for a minimum of 12 weeks of treatment prior to Day 1
- •At screening confirmed diagnosis of PBC
- •Model for end-stage liver disease (MELD)-Na scores of 6 to 24
排除标准
- •Clinically significant or history of acute or chronic liver disease of an etiology other than PBC
- •Patients with a diagnosis of overlapping PBC and autoimmune hepatitis
- •History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms.
- •Presumptive or diagnosed infection that requires systemic therapy within 12 weeks of Screening and through Day 1
- •Female participants who are pregnant or nursing
- •Screening electrocardiogram (ECG) that demonstrates a QT interval ≥ 500 msec, or any other significant ECG finding with clinically significant abnormalities as determined by the Investigator
- •Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus - ribonucleic acid (HCV RNA), or anti human immunodeficiency virus (HIV) antibody
- •Any non-hepatic acute or chronic condition that, in the opinion of the Investigator, would limit the patient's ability to complete and/or participate in the study or compromise the integrity of the data
- •Has experienced an illness that is considered by the Investigator to be clinically significant within 2 weeks before administration of investigational product
- •Clinically relevant drug or alcohol abuse within 6 months of Screening. A positive drug screen will exclude participants unless it can be explained by a prescribed medication
- •Use of obeticholic acid (OCA), any drug of the same class, or fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) within 30 days of Baseline
- •Use of an experimental or unapproved treatment for PBC within 30 days of Baseline
- •Clinically evident complication(s) of cirrhosis and portal hypertension that required either emergency room visit, hospital admission or both during the 12 week period prior to investigational product administration
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part A: Cohort 1 - CP-A Without PHT (Seladelpar 10 mg)
Participants with primary biliary cholangitis (PBC) and a Child-Pugh (CP) classification of CP-A (score 5 to 6) without portal hypertension (PHT) will receive a single dose of seladelpar 10 mg, orally, on Day 1.
干预措施: Seladelpar (Drug)
Part A: Cohort 2 - CP-A With PHT (Seladelpar 10 mg)
Participants with PBC and a CP classification of CP-A (score 5 to 6) with PHT will receive a single dose of seladelpar 10 mg, orally, on Day 1.
干预措施: Seladelpar (Drug)
Part A: Cohort 3 - CP-B (Seladelpar 10 mg)
Participants with PBC and a CP classification of CP-B (score 7 to 9) will receive a single dose of seladelpar 10 mg, orally, on Day 1.
干预措施: Seladelpar (Drug)
Part A: Cohort 4 - CP-C (Seladelpar 10 mg)
Participants with PBC and a CP classification of CP-C (score 10 to 12) will receive a single dose of seladelpar 10 mg, orally, on Day 1.
干预措施: Seladelpar (Drug)
Experimental: Part B: Cohort 2 - CP-A With PHT (Seladelpar 5 mg or 10 mg)
Participants with PBC and a CP classification of CP-A (score 5 to 6) with PHT, who complete Part A, will receive seladelpar 10 mg or 5 mg, orally, once daily, for 28 days. Doses for Part B will be chosen based on exposure from a single dose in Part A for individual participants.
干预措施: Seladelpar (Drug)
Experimental: Part B: Cohort 3 - CP-B (Seladelpar 5 mg or 10 mg)
Participants with PBC and a CP classification of CP-B (score 7 to 9), who complete Part A, will receive seladelpar 10 mg or 5 mg, orally, once daily, for 28 days. Doses for Part B will be chosen based on exposure from a single dose in Part A for individual participants.
干预措施: Seladelpar (Drug)
结局指标
主要结局
Evaluate maximum concentration (Cmax) of seladelpar and metabolites
时间窗: 17 weeks
Evaluate the time to reach Cmax (Tmax) of seladelpar and metabolites
时间窗: 17 weeks
Evaluate area under the concentration curve versus time curve of seladelpar and metabolites
时间窗: 17 weeks
Evaluate the amount of seladelpar excreted in the urine (Ae)
时间窗: 17 weeks
Evaluate safety and tolerability as assessed by the incidence of treatment emergent adverse events and serious treatment emergent adverse events across child pugh treatment groups
时间窗: 17 weeks
Part A: Pharmacokinetic (PK) Parameter: Cmax of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose
Cmax is defined as the maximum observed plasma concentration of the study drug.
Part A: PK Parameter: Tmax of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose
Tmax is defined as the time to reach the maximum observed plasma concentration of the study drug.
Part A: PK Parameter: AUC0-t of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose
AUC0-t is defined as area under the concentration--time curve from time zero to the last measurable concentration.
Part A: PK Parameter: AUC0-inf of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose
AUC0-inf is defined as area under the concentration--time curve from time zero extrapolated to infinity, calculated as AUC0-t+Ct/Kel, where: Ct = the last measurable concentration and Kel = elimination rate constant.
Part B: PK Parameter: Cmax of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose
Cmax is defined as the maximum observed plasma concentration of the study drug.
Part B: PK Parameter: Cmax,ss of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose
Cmax,ss is defined as the steady-state maximum observed plasma concentration of the study drug at Day 28.
Part B: PK Parameter: Tmax of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose
Tmax is defined as the time to reach the maximum observed plasma concentration of the study drug.
Part B: PK Parameter: Tmax,ss of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose
Tmax,ss is defined as the steady-state time to reach maximum observed plasma concentration of the study drug at Day 28.
Part B: PK Parameter: AUC0-24 of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose
AUC0-24 is defined as area under the concentration-time curve from time zero to 24 hours.
Part B: PK Parameter: AUC0-tau of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose
AUCtau is defined as the area under the drug concentration versus time curve over the dosing interval.
Part B: PK Parameter: RCmax of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose
RCmax is defined as the accumulation ratio based on Cmax, calculated as Cmax on Day 28/ Day 1.
Part B: PK Parameter: RAUC0-t of Seladelpar and Its Metabolites (M1, M2, and M3)
时间窗: Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose
RAUC0-t is defined as the accumulation ratio based on AUC0-t, calculated as AUC0-tau on Day 28/ AUC0-24 on Day 1 for participants with dose once a day.
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs
时间窗: Part A: Up to Week 5; Part B: Up to Week 8
An adverse event (AE) was defined as any medical occurrence in a participant administered to a pharmaceutical product in a clinical study, regardless of a causal relationship with this treatment. TEAEs were defined as AEs that commenced or worsened on or after the time of study drug administration in Part A until up to 30 days after study drug administration in Part A or before the first study drug administration in Part B (whichever is earlier). For Part B, TEAEs are defined as AEs that commence or worsen on or after the time of first study drug administration in Part B until up to 30 days after the last study drug administration in Part B. A drug-related TEAE was defined as TEAE which was related (reported as 'possible', 'probable', or 'definite') to study drug. Percentages were rounded off.
Percentage of Participants Who Experienced Any Grade and Grade 3 or 4 TEAEs
时间窗: Part A: Up to Week 5; Part B: Up to Week 8
TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. The percentage of participants with any severity grade and severity grade of 3 or 4 were reported. Percentages were rounded off.
Percentage of Participants Who Experienced TEAEs of Special Interest
时间窗: Part A: Up to Week 5; Part B: Up to Week 8
TEAEs of special interest for this study were defined as AEs that met CTCAE version 5.0 or the most recent version Grade 2 criteria or higher for AEs of elevated alanine transaminase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine kinase, lipase, or serum creatinine. Hepatic decompensation clinical events including ascites, jaundice, esophageal variceal bleeding, and hepatic encephalopathy, were also defined as TEAEs of special interest for this study. Percentages were rounded off.
Percentage of Participants With Clinically Significant Changes in Vital Signs
时间窗: Part A: Up to Day 4; Part B: Up to Day 31
Vital signs (including oral temperature, respiratory rate, seated blood pressure \[diastolic and systolic\], and heart rate) were evaluated. Percentage of participants with clinically significant changes in vital signs evaluations was reported. The clinically significant changes were based on investigator's judgement.
Percentage of Participants With Abnormal Clinically Significant 12-Lead Electrocardiogram (ECG) Findings
时间窗: Part A: Up to Day 4; Part B: Up to Day 28
ECG measurements included the parameters of heart rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and QT interval corrected for heart rate according to Fridericia's formula (QTcF). Per protocol, ECG findings were classified in 1 of 3 categories: normal, abnormal but not clinically significant, or abnormal and clinically significant. Any abnormality in ECG assessments which were deemed clinically significant by the investigator were reported.
Percentage of Participants Who Experienced Laboratory Abnormalities
时间窗: Part A: Up to Day 4; Part B: Up to Day 31
Clinical laboratory parameters included biochemistry, hematology, coagulation, and urinalysis. Abnormal laboratory values were graded according to the NCI CTCAE version 5.0.Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. The percentage of participants with a shift of ≥ 2 NCI CTCAE grade from baseline was reported.
次要结局
- Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: PK Parameter (Urine): Ae0-t of Seladelpar and Its Metabolites (M1, M2, and M3)(Day 1: Predose; 0-6 h, and 6-12 h postdose)
- Part A: PK Parameter (Urine): CLR of Seladelpar(Day 1: Predose; 0-6 h, and 6-12 h postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar Cmax and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-inf and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part A: Rsq Between Plasma Seladelpar AUC0-t and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose)
- Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Albumin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Prothrombin Time(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Bilirubin(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar Cmax and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-t and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose)
- Part B: Rsq Between Plasma Seladelpar AUC0-inf and CP Score(Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose)