Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function
Condition: Infections, Bacterial
MeSH terms: Bacterial Infections
Intervention: Gepotidacin
Intervention description: It is an immediate-release tablet (1500 mg (2 x 750 mg), containing gepotidacin (free base) an inactive formulation excipients.
Intervention MeSH terms: Gepotidacin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Masking description: There will be no masking, as this is an open-label study.
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Child-Pugh classification; Open label; Hepatic Impairment; Gepotidacin

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  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 must be able to abstain from alcohol and limit use of nicotine and/or
             nicotine-containing products (up to 5 cigarettes/day is acceptable for subjects with
             hepatic impairment) for 24 hours before the start of dosing until after collection of
             the final PK sample. A positive alcohol or cotinine test is not exclusionary for
             subjects with hepatic impairment.

          -  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.

          -  Subject with normal hepatic function has a baseline corrected QT interval using the
             Fridericia formula (QTcF) of >450 milliseconds (msec) and subject with hepatic
             impairment has a baseline QTcF of >480 msec.

          -  Donation of blood in excess of 500 milliliter (mL) within 12 weeks prior to dosing or
             participation in the study would result in donation of blood or blood products in
             excess of 500 mL within a 56-day period.

          -  Subject is unable to comply with all study procedures, in the opinion of the
             investigator.

          -  Subject should not participate in the study, in the opinion of the investigator or
             Sponsor.

          -  Subjects with a pre-existing condition (except hepatic impairment) interfering with
             normal gastrointestinal (GI) anatomy or motility that could interfere with the
             absorption, metabolism, and/or excretion of the study drugs. Subjects with a history
             of inflammatory bowel disease should be excluded. Subjects with a history of
             pepticulceration or pancreatitis within the preceding 6 months of screening, should be
             excluded.

          -  Subject with any previous GI surgery (except appendectomy or gall bladder removal >3
             months prior to Screening) may be enrolled in this study only if, in the opinion of
             the investigator and the medical monitor, it is not expected to interfere with the
             study procedures or to pose an additional safety risk to the subject.

          -  Subject receiving lactulose who are medically unable to halt lactulose administration
             from 8 hours before dosing with study drug to 4 hours after dosing with study drug.

          -  Subjects with clinically active severe encephalopathy (grade 3 or 4) as judged by the
             investigator or significant central nervous system disease (e.g., dementia or
             seizures) which the investigator considers will interfere with the informed consent,
             conduct, completion, or results of this trial or constitutes an unacceptable risk to
             the subject. Subjects with a prior history of severe encephalopathy, who are currently
             treated for this condition will receive the appropriate score for encephalopathy.

          -  Subjects with estimated creatinine clearance (Clcr) <=50 mL/minute (calculated by the
             Cockcroft-Gault Formula). If the result calculated by Cockcroft-Gault is between 40
             and 50 mL/minute, then the site may complete a 24-hour urine collection to more
             specifically calculate the Clcr. A Clcr value <=50 mL/minute via 24-hour urine
             collection is also exclusionary.

          -  History of gastric or esophageal variceal bleeding within the past 6 months and for
             which varices have not been adequately treated with medication and/or surgical
             procedures.

          -  Subjects with electrolyte imbalance whose serum sodium levels are <=125 millimole per
             Liter (mmol/L); potassium levels are <=2.5 mmol/L; or calcium levels are <=6.1 mmol/L.

          -  Presence of hepatopulmonary or hepatorenal syndrome.

          -  Primary cholestatic liver diseases.

          -  History of liver transplantation or subjects in the severe hepatic impairment group
             that are expecting a liver transplant during the study participation period.

          -  Subjects with signs of active bacterial infection (including active spontaneous
             bacterial peritonitis).

          -  Subjects with transjugular intrahepatic portosystemic shunt placement within the past
             3 months.

          -  Subjects with unstable cardiac function or subjects with hypertension whose blood
             pressure, that is not well controlled (based on the investigator's discretion).

          -  Diabetic subjects whose diabetes that is not controlled (based on the investigator's
             discretion).