Linerixibat and Obeticholic Acid Drug Interaction Study in Healthy Subjects

NCT04053023 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 206224
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

In participants with inadequate response/intolerance to ursodeoxycholic acid (UDCA) taking obeticholic acid (OCA) who experience pruritus (due to primary biliary cholangitis \[PBC\], OCA, or both) the addition of linerixibat to OCA therapy may be considered following marketing approval. It is therefore important to characterize any potential effect of linerixibat on the pharmacokinetics of OCA in humans at clinically relevant dosages. Accordingly, a drug-drug interaction (DDI) study with linerixibat (potential perpetrator) and OCA (potential victim) will be conducted to inform both future clinical trials with linerixibat and the potential concomitant administration of these drugs in a clinical setting. This is a single-center, one part (with optional second part) open-label, single sequence crossover, drug interaction study to investigate the effect of linerixibat on plasma concentrations of OCA and OCA conjugates in healthy participants. Approximately 19 participants will be enrolled in part A and further 19 participants in part B (if performed) in the study and will have a phone call follow-up till 7-14 days post-last linerixibat dose.

Conditions

Cholestasis

Keywords

linerixibat (GSK2330672), obeticholic acid, drug interaction, primary biliary cholangitis, pharmacokinetics

Outcome Measures

Primary Outcomes (16)

• Part A- Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-t]) for Total-OCA at Steady State: OCA Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. Pharmacokinetic (PK) Parameters Population consisted of all participants for whom pharmacokinetic parameters were derivable.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part A- AUC(0-t) for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part A- Area Under the Concentration-time Curve From Time 0 to 24 Hour (AUC[0-24]) for Total-OCA at Steady State: OCA Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part A- AUC(0-24) for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part A- Maximum Observed Concentration (Cmax) for Total-OCA at Steady State: OCA Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part A- Cmax for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part A- Average Trough Concentration (Ctrough) for Total-OCA at Steady State: OCA Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. Average of Ctrough measurement from study Days 17, 18 and 19 has been presented.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part A- Average Ctrough for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. Average of Ctrough measurement from study Days 35, 36, 37 and 38 has been presented.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part B- AUC(0-t) for Total-OCA at Steady State: OCA Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part B- AUC(0-t) for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part B- AUC(0-24) for Total-OCA at Steady State: OCA Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part B- AUC(0-24) for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part B- Cmax for Total-OCA at Steady State: OCA Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part B- Cmax for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part B- Ctrough for Total-OCA at Steady State: OCA Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part B- Ctrough for Total-OCA at Steady State: OCA + Linerixibat Arm

  Blood samples were planned to be collected at indicated time points for pharmacokinetic analysis of total-OCA.

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

Secondary Outcomes (124)

• Part A- Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total-OCA: OCA Arm

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

• Part A- Tmax for Total-OCA: OCA + Linerixibat Arm

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose

• Part A- Assessment of Steady State Using Ctrough of Total-OCA: OCA Arm

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 hours and 24 hours (Day 19) post-dose

• Part A- Assessment of Steady State Using Ctrough of Total-OCA: OCA + Linerixibat Arm

  Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 hours and 24 hours (Day 38) post-dose

• Part A- AUC(0-t) for OCA: OCA Arm

  Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

Study Arms (1)

Participants receiving obeticholic acid and linerixibat

EXPERIMENTAL

In Part A, participants will be administered one tablet of 10 milligrams (mg) obeticholic acid once daily continuously for 37 days (study Day 1 to study Day 37). Two tablets of 45 mg linerixibat will be administered twice daily from study Day 20 to study Day 37. 1 tablet of 45 mg linerixibat will be administered on Day 38. After evaluation of Part A, if optional part B is conducted, participants will be administered linerixibat and obeticholic acid at an alternative dosing regimen.

Drug: GSK2330672 (linerixibat); Drug: Obeticholic acid

Interventions

GSK2330672 (linerixibat) DRUG

GSK2330672 is available as a tablet with unit dose strength of 45 mg.

Participants receiving obeticholic acid and linerixibat

Obeticholic acid DRUG

Obeticholic acid is available as a tablet with a unit dose strength of 10 mg (or 5 mg dependent on evaluation of Part A).

Participants receiving obeticholic acid and linerixibat

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between 18 and 80 years of age 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 participant 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 in consultation with the GlaxoSmithKline (GSK) medical monitor and documents in the source documentation that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes.
• Body weight \> 50 kilogram (kg) and body mass index (BMI) within the range 18.5 to 32 kg per square meter (inclusive).
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.

You may not qualify if:

• Any active dermatologic disorder leading to or with the potential to cause pruritus or a recent history of unexplained clinically significant itching locally or generally within the prior 3 months
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) and/or confirmed hepatocellular carcinoma or biliary cancer
• Participants with a history of cholecystectomy
• Current symptomatic cholelithiasis or inflammatory gall bladder disease
• 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 (within 1 month of screening visit), or chronic history of clinically significant diarrhea
• Lymphoma, leukaemia, 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 (e.g. psychiatric disorder, senility, dementia, or other condition), clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant 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 \>14 units for females and \>21 units for males. One unit is equivalent to 8 gram of alcohol: a glass (approximately \[\~\] 240 milliliter \[mL\]) of beer, 1 small glass (\~100 mL) of wine or 1 (\~25 mL) measure of spirits
• History of or regular use of tobacco- or nicotine-containing products (confirmed by smokerlyzer test) in the 3 months prior to screening.
• Administration of any IBAT inhibitor (including linerixibat) or OCA in the 3 months prior to screening
• Past or intended use of over-the-counter or prescription medication (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless approved by the investigator in conjunction with GSK medical monitor.
• Current enrollment in a clinical trial, recent participation in a clinical trial and has received an investigational product within 30 days (or 5 half-lives of previous trial intervention, whichever is longer) before the first dose in the current study

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 0GG, United Kingdom

Location

MeSH Terms

Conditions

Cholestasis; Liver Cirrhosis, Biliary

Interventions

3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid; obeticholic acid

Condition Hierarchy (Ancestors)

Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Cholestasis, Intrahepatic; Liver Diseases; Liver Cirrhosis; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This will be a non-randomized study. Eligible subjects will receive OCA and OCA+linerixibat in a fixed sequence.

Study Record Dates

• First Submitted: August 8, 2019
• First Posted: August 12, 2019
• Study Start: August 27, 2019
• Primary Completion: November 25, 2019
• Study Completion: November 25, 2019
• Last Updated: July 24, 2020
• Results First Posted: July 24, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a data sharing agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (1)