Clinical trial NCT03992014: Pharmacokinetics (PKs) and Metabolism of Radiolabelled Linerixibat
Official title: A Two-period Study in Healthy Male Participants to Determine the Pharmacokinetics, Balance/Excretion, and Metabolism of [14C]-Linerixibat Following a Single Intravenous Radiolabeled Microtracer Dose (Concomitant With a Non-radiolabeled Oral Dose) and a Single Oral Radiolabeled Dose
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cholestasis
Keywords: [14C]-linerixibat
GSK2330672
Microtracer dose
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-06-19
Enrollment: 6
Sex: MALE
Minimum age (years): 30
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Subjects will receive linerixibat tablets concomitantly with \[14C\]-linerixibat IV infusion in treatment Period 1 and \[14C\]-linerixibat oral solution in treatment Period 2.
Primary purpose: TREATMENT

Brief summary: Absorption, metabolism and excretion of linerixibat have been studied in previous clinical trials. However, no dedicated clinical studies of drug absorption, metabolism, and excretion have been conducted for linerixibat. The purpose of this study is to determine the PK, balance/excretion, and metabolism of radiolabeled 14 Carbon \[14C\]-linerixibat following a single intravenous (IV) radiolabeled microtracer dose (concomitant with a non-radiolabeled oral dose) and a single oral radiolabeled dose. This is a single group, two period, single sequence, and mass balance study will enroll 6 healthy male subjects. Each subject will be involved in the study for up to 10 weeks which includes screening period, two treatment periods (treatment Periods 1 and 2), separated by about 7 days (at least 13 days between oral doses), and a follow-up visit 1-2 weeks after the last assessment in treatment Period 2.


Eligibility criteria: Inclusion Criteria

* Aged 30 to 55 years, inclusive, at the time of signing the informed consent.
* Healthy, as determined by the investigator or medically qualified designee, based on a medical evaluation including medical history, physical examination, vital signs, laboratory tests, and ECG. A subject with a clinical abnormality or laboratory parameter (i.e., outside the reference range for the population being studied), which is not specifically listed in the eligibility criteria, may be included only if the investigator agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
* History of regular bowel movements (averaging one or more bowel movements per day).
* Non-smoker, or ex-smoker who hasn't regularly smoked for the 6 months before screening.
* Body weight of 50 kilogram and above, and body mass index (BMI) within the range 19.0 to 31.0 kilogram per square meter (kg/m\^2) (inclusive).
* Male only. Subjects must agree to use contraception as follows: subjects with female partners of childbearing potential must agree to use a condom from the time of first dose of study intervention until 1 month after their last dose.
* Capable of giving signed informed consent.

Exclusion Criteria

* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Subjects with a history of cholecystectomy must be excluded.
* Significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
* Any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history) clinical laboratory tests, or 12-lead ECG.
* Current episode, recent history, or chronic history of diarrhoea.
* Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
* Any current medical condition (example given \[e.g.\], psychiatric disorder, senility, dementia, or other condition), clinical or laboratory abnormality, or examination finding that the investigator considers would put the subjects at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study.
* Regular use of known drugs of abuse or history of drug abuse or dependence within 6 months of the study.
* Regular alcohol consumption within 6 months prior to the study defined as an average weekly intake of \>21 units. One unit is equivalent to 8 gram of alcohol: a glass (approximately 240 mL) of beer, 1 small glass (approximately 100 mL) of wine or 1 (approximately 25 mL) measure of spirits.
* History of or regular use of tobacco- or nicotine-containing products in the 6 months prior to screening.
* Past or intended use of over-the-counter or prescription medication, including analgesics (e.g., paracetamol), herbal medications, or grapefruit and Seville orange juices within 14 days prior to the first dose of study intervention until completion of the follow-up visit.
* Administration of any other Ileal bile acid transporter (IBAT) inhibitor in the 3 months prior to screening.
* Current enrolment in a clinical trial; recent participation in a clinical trial and has received an investigational product within 3 months before the first dose in the current study.
* Exposure to more than 4 new chemical entities within 12 months before the first dose in the current study.
* Participation in a clinical trial involving administration of 14C-labelled compound(s) within the last 12 months. A subjects previous effective dose will be reviewed by the medical investigator to ensure there is no risk of contamination/carryover into the current study.
* Received a total body radiation dose of greater than 10.0 millisievert (upper limit of International Commission on Radiological Protection \[IRCP\] category II) or exposure to significant radiation (e.g., serial x-ray or computed tomography \[CT\] scans, barium meal, etc.) in the 3 years before this study.
* Alanine transaminase (ALT) \>1.5\* upper limit of normal (ULN).
* Bilirubin \>1.5\*ULN (isolated bilirubin \>1.5\*ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent \[%\]).
* Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening or within 3 months before the first dose of study intervention.
* Screening estimated glomerular filtration rate (eGFR) \<45 milliliter per minute per 1.73 square meter (mL/min/1.73m\^2) based on the Modification of Diet in Renal Disease (MDRD) Study equation.
* Positive pre-study drug/alcohol screen.
* Urinary cotinine levels indicative of smoking.
* Positive human immunodeficiency virus (HIV) antibody test.
* QT duration corrected for heart rate by Fridericia's formula \>450 millisecond on ECG performed at Screening
* At screening or prior to the first dose, a supine blood pressure that is persistently higher than 140/90 millimeters of mercury (mmHg) taken in triplicate, unless deemed not clinically significant by the investigator.
* At screening or prior to the first dose, a supine mean heart rate outside the range of 40-100 beats per minute, unless deemed not clinically significant by the investigator.
* Has had an occupation which requires monitoring for radiation exposure, nuclear medicine procedures, or excessive x-rays within the past 12 months.
* Unable to refrain from consumption of prohibited food and drinks from 7 days before the first dose of study medication until the follow up visit.
* Loss of more than 400 mL blood during the 3 months before screening, e.g. as a blood donor, or plan to donate blood or blood products in the 3 months after the end of the trial.
* Unwillingness or inability to follow the procedures outlines in the protocol, including the use of the string bile collection device.
* History of sensitivity to linerixibat, or their components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline Medical Monitor, contraindicates their participation.

Primary outcomes:
measure: Period 1: Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of Linerixibat and [14C]-Linerixibat Following Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: AUC(0-inf) of [14C]-Linerixibat Following Administration of Oral Dose of [14C]-Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-t]) of Linerixibat and [14C]-Linerixibat Following Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: AUC(0-t) of [14C]-Linerixibat Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Maximum Observed Concentration (Cmax) of Linerixibat and [14C]-Linerixibat Following Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: Cmax of [14C]-Linerixibat Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Time of Occurrence of Cmax (Tmax) of Linerixibat and [14C]-Linerixibat Following Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: Tmax of [14C]-Linerixibat Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Terminal Phase Half-Life (t1/2) of Linerixibat and [14C]-Linerixibat Following Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: t1/2 of [14C]-Linerixibat Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: AUC(0-inf) of Total Radioactivity Following IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: AUC(0-inf) of Total Radioactivity Following Administration of Oral Dose of [14C]-Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: AUC(0-t) of Total Radioactivity Following IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: AUC(0-t) of Total Radioactivity Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Cmax of Total Radioactivity Following IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: Cmax of Total Radioactivity Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Tmax of Total Radioactivity Following IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: Tmax of Total Radioactivity Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: t1/2 of [14C]-Linerixibat for Total Radioactivity Following IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 2: t1/2 of [14C]-Linerixibat for Total Radioactivity Following Administration of Oral Dose of [14C] Linerixibat Solution
timeFrame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Volume of Distribution at Steady State (Vss) of [14C]-Linerixibat Following Administration of IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Total Plasma Clearance (CL) of [14C]-Linerixibat Following Administration of IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Hepatic Clearance (CLh) of [14C]-Linerixibat Following Administration of IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Absolute Oral Bioavailability (F) of Linerixibat Following Administration of Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Percentage of Drug Escaping First-pass Hepatic Clearance (Fh) of Linerixibat Following Administration of Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Percentage of Drug Absorbed (Fa) for Linerixibat Following Administration of Oral Dose of Linerixibat and IV Dose of [14C]-Linerixibat
timeFrame: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Period 1: Summary of Mean Cumulative Total Recovery (Percentage Excreted) in Urine Following Administration of IV Dose of [14C]-Linerixibat.
timeFrame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144 and 0-168 hours post-dose
measure: Period 2: Summary of Mean Cumulative Total Recovery (Percentage Excreted) in Urine Following Administration of Oral Dose of [14C]-Linerixibat
timeFrame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144 and 0-168 hours post-dose
measure: Period 1: Summary of Mean Cumulative Total Recovery (Percentage Excreted) in Feces Following Administration of IV Dose of [14C]-Linerixibat
timeFrame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144 and 0-168 hours post-dose
measure: Period 2: Summary of Mean Cumulative Total Recovery (Percentage Excreted) in Feces Following Administration of Oral Dose of [14C]-Linerixibat
timeFrame: 0-24, 0-48, 0-72, 0-96, 0-120, 0-144 and 0-168 hours post-dose
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 34 days
measure: Number of Participants With Worst Case Hematology Results Relative to Normal Range
timeFrame: Up to 34 days
measure: Number of Participants With Worst Case Chemistry Results Relative to Normal Range
timeFrame: Up to 34 days
measure: Number of Participants With Abnormal Urinalysis Results by Dipstick Method
timeFrame: Up to 34 days
measure: Number of Participants With Clinically Significant Abnormal Findings for Electrocardiogram (ECG) Parameters
timeFrame: Up to 34 days
measure: Period 1: Change From Baseline in Diastolic Blood Pressure (DBP) at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Period 2: Change From Baseline in DBP at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Change From Baseline in DBP at Follow-up Visit (Day 34)
timeFrame: Baseline and Day 34 (post Day 1 of Period 1 dosing)
measure: Period 1: Change From Baseline in Pulse Rate at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Period 2: Change From Baseline in Pulse Rate at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Change From Baseline in Pulse Rate at Follow-up Visit (Day 34)
timeFrame: Baseline and Day 34 (post Day 1 of Period 1 dosing)
measure: Period 1: Change From Baseline in Systolic Blood Pressure (SBP) at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Period 2: Change From Baseline in SBP at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Change From Baseline in SBP at Follow-up Visit (Day 34)
timeFrame: Baseline and Day 34 (post Day 1 of Period 1 dosing)
measure: Period 1: Change From Baseline in Respiratory Rate at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Period 2: Change From Baseline in Respiratory Rate at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Change From Baseline in Respiratory Rate at Follow-up Visit (Day 34)
timeFrame: Baseline and Day 34 (post Day 1 of Period 1 dosing)
measure: Period 1: Change From Baseline in Tympanic Membrane Temperature at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Period 2: Change From Baseline in Tympanic Membrane Temperature at Indicated Time-points
timeFrame: Baseline, Day 1 (4 Hours) and Day 8
measure: Change From Baseline in Tympanic Membrane Temperature at Follow-up Visit (Day 34)
timeFrame: Baseline and Day 34 (post Day 1 of Period 1 dosing)
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: