Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function

NCT03562117 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 117352
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

This is a two-part study which will evaluate the PK, safety, and tolerability of a single 1500 milligram (mg) oral dose of gepotidacin in subjects with normal hepatic function and in subjects with mild, moderate, and severe hepatic impairment. In Part 1, subjects with moderate hepatic impairment and subjects with normal hepatic function will be enrolled. Matching subjects with normal hepatic function in Part 1 (Group D), will be enrolled following the completion of all Day 3 assessments of the respective matched, hepatically impaired subject. In Part 2, subjects with mild (optional) and severe hepatic impairment and subjects with normal hepatic function will be enrolled concurrently based on the PK, safety, and tolerability data of Part 1. Subjects with mild hepatic impairment, may be studied if there is a significant difference in PK between subjects with moderate hepatic impairment and subjects with normal hepatic function. Subjects with severe hepatic impairment, will be studied in Part 2, provided that, the PK objectives are achieved in Part 1. A totals of 48 subjects, are planned to be enrolled in the study. The study duration is approximately of 44 days from Screening to Follow-up visit. The results from this study will enable the development of appropriate dosing recommendations in subjects with impaired hepatic function.

Conditions

Infections, Bacterial

Keywords

Child-Pugh classification; Open label; Hepatic Impairment; Gepotidacin

Outcome Measures

Primary Outcomes (2)

• Area Under the Plasma Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinity (AUC[0-inf]) for Plasma Gepotidacin

  Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate pharmacokinetic (PK) parameters. PK parameter population consist of all participants in the PK Population, for whom valid and evaluable PK parameters were derived. This population was used in the assessment and characterization of PK parameters.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

• Maximum Observed Concentration (Cmax) for Plasma Gepotidacin

  Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Secondary Outcomes (25)

• AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC [0-t]) for Plasma Gepotidacin

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

• Time to First Occurrence (Tmax) of Cmax for Plasma Gepotidacin

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

• Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) for Plasma Gepotidacin

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

• Apparent Oral Clearance (CL/F) for Plasma Gepotidacin

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

• Apparent Volume of Distribution of the Terminal Phase (Vz/F) for Plasma Gepotidacin

  Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose

Study Arms (5)

Normal Hepatic function, Part 1 (Group D)

EXPERIMENTAL

The eligible subjects, with normal hepatic function, in this arm will receive a single oral dose of gepotidacin as 1500 milligram (mg), administered as 2 × 750 mg tablets on Day 1.

Drug: Gepotidacin

Moderate hepatic impairment, Part 1 (Group B)

EXPERIMENTAL

The subjects in this arm, will be the one's with a Child-Pugh score of 7 to 9, and will receive a single oral dose of gepotidacin, as 1500 mg, administered as 2 × 750 mg tablets on Day 1.

Drug: Gepotidacin

Mild hepatic impairment, Part 2 (Group A)

EXPERIMENTAL

The subjects in this arm, will be the one's with a Child-Pugh score of 5 to 6, and will receive a single oral dose of gepotidacin, as 1500 mg, administered as 2 × 750 mg tablets on Day 1. This will be optional arm.

Drug: Gepotidacin

Severe hepatic impairment, Part 2 (Group C)

EXPERIMENTAL

The subjects in this arm, will be the one's, with a Child-Pugh score of 7 to 9, and will receive a single oral dose of gepotidacin, as 1500 mg, administered as 2 × 750 mg tablets, on Day 1.

Drug: Gepotidacin

Normal Hepatic function, Part 2 (Group E)

EXPERIMENTAL

The eligible subjects, with normal hepatic function, will be matching with those enrolled in Part1, and will receive a single oral dose of gepotidacin as 1500 mg, administered as 2 × 750 mg tablets on Day 1.

Drug: Gepotidacin

Interventions

Gepotidacin DRUG

It is an immediate-release tablet (1500 mg (2 x 750 mg), containing gepotidacin (free base) an inactive formulation excipients.

Mild hepatic impairment, Part 2 (Group A); Moderate hepatic impairment, Part 1 (Group B); Normal Hepatic function, Part 1 (Group D); Normal Hepatic function, Part 2 (Group E); Severe hepatic impairment, Part 2 (Group C)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
• Healthy subjects must be in clinically stable health as determined by the investigator based on medical history, clinical laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign measurements, 12-lead ECG results, and physical examination findings.
• Hepatically impaired subjects must have chronic (\>6 months), stable (no acute episodes of illness within the previous 1 month prior to screening due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology. Subjects must also remain stable throughout the Screening period.
• Hepatically impaired subjects, will be classified, using the Child-Pugh classification system. Subjects must have, a Child-Pugh score, of 5 to 6 (mild hepatic impairment), 7 to 9 (moderate hepatic impairment), or 10 to 15 (severe hepatic impairment), with known medical history of liver disease (with or without a known history of alcohol abuse), and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, computed tomography scan, magnetic resonance imaging, or ultrasonography) associated with unambiguous medical history. If imaging study, or biopsy is not available, then the subject should have one of the following: Physical findings such as hepatomegaly, ascites, palmar erythema, spider angiomata, abdominal venous collaterals, gynecomastia, or other physical manifestations of hepatic disease Or Laboratory findings: ALT or AST elevation (\> upper limit of normal \[ULN\]), alkaline phosphatase, or total bilirubin, or international normalized ratio (INR) elevation (\>ULN) or an albumin value that is below the lower limit of normal laboratory reference range.
• Subjects with hepatic impairment may be taking medications, which in the opinion of the investigator, are believed to be therapeutic, and these medications should not interfere with the conduct of the study. Subjects with hepatic impairment should be on stable regimen of chronic medications for at least 7 days prior to dosing until completion of the Follow-Up Visit.
• Subjects with hepatic impairment must have platelet counts of 30,000 × 109/Liter of blood and have not had any major bleeding episodes within the past 6 months.
• Body weight \>=45 kilogram (kg) and body mass index (BMI) within the range 18.5 to 40 kg/meter\^2 (inclusive).
• Male subjects must agree to use contraception, as protocol from Day -1 until completion of the Follow-up Visit or, female subject will be eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applied Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive guidance from 30 days prior to study drug administration and until completion of the Follow-up Visit.
• Capable of giving signed informed consent.

You may not qualify if:

• Subject has a clinically significant abnormality in past medical history or at the Screening physical examination (excluding hepatic insufficiency and other related medical conditions within the hepatically impaired populations, which should be stable for at least 1 month before study drug administration), that in the investigator's opinion, may place the subject at risk or interfere with outcome variables of the study. This includes, but is not limited to, history or current significant cardiac, renal, neurologic, gastrointestinal, respiratory, hematologic, or immunologic disease.
• Subject has any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study drug, or any other condition that may place the subject at risk, in the opinion of the investigator.
• Female subject, has a positive pregnancy test result or is lactating at Screening or upon admission to the clinic.
• Subject has used a systemic antibiotic within 7 days of Screening.
• Subject has a confirmed history of Clostridium (C) difficile infection or a positive C. difficile toxin test, within 2 months before Screening.
• Subject has a history of drug and/or alcohol abuse within 6 months before Screening, as determined by the investigator, or subject has a positive drug screen at Screening or upon admission to the clinic. For subjects with hepatic impairment, and a positive drug screen result related to the use of prescription medications, is allowed per investigator review and approval, and tetrahydrocannabinol use is allowed per investigator review and approval.
• History of sensitivity to any of the study drugs, components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GSK medical monitor, contraindicates their participation.
• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic uses heparin to maintain intravenous cannula patency).
• Subject has used medications known to affect the elimination of serum creatinine (example (e.g); trimethoprim or cimetidine) or competitors of renal tubular secretion (e.g., probenecid) within 30 days before dosing.
• Subject must abstain from taking prescription or nonprescription drugs (including vitamins and dietary or herbal supplements), unless specified, within 7 days (or 14 days if the drug is a potential strong enzyme inducer) or 5 half-lives (whichever is longer) prior to study drug administration until completion of the Follow-Up Visit, unless, in the opinion of the investigator and Sponsor, the medication will not interfere with the study. Any exceptions (including subjects with hepatic impairment that will be on medications during the study), will be discussed with the sponsor or medical monitor on a case-by-case basis and the reasons will be documented.
• Previous exposure to gepotidacin, within 12 months prior to study drug administration.
• Subject has participated in a clinical trial and has received an investigational product within the following time period prior to study drug administration in the current study: 30 days, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer).
• Subject with normal hepatic function has presence of hepatitis B surface antigen or positive hepatitis C antibody test result at Screening or within 3 months prior to study drug administration. Subject with hepatic impairment has evidence of recent, acute infection with hepatitis B and/or hepatitis C within preceding 6 months. Hepatically impaired subjects with chronic hepatitis B or C (duration \>6 months) will be eligible for enrolment.
• A positive test for human immunodeficiency virus antibody.
• Subject has clinically significant abnormal findings in serum chemistry, hematology, or urinalysis results obtained at Screening or Day -1, other than those associated with underlying hepatic conditions or other stable medical conditions consistent with the disease process in subjects with hepatic impairment.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Biomedical Advanced Research and Development Authority: collaborator

Study Sites (2)

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

Orlando, Florida, 32809, United States

Location

MeSH Terms

Conditions

Bacterial Infections

Interventions

gepotidacin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

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
• Masking Details: There will be no masking, as this is an open-label study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2018
• First Posted: June 19, 2018
• Study Start: June 14, 2018
• Primary Completion: December 26, 2018
• Study Completion: December 26, 2018
• Last Updated: April 12, 2021
• Results First Posted: December 17, 2019

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• 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

US (2)