Pharmacokinetic Study of Gepotidacin in Subjects With Varying Degrees of Renal Impairment and in Subjects With Normal Renal Function
Condition: Infections, Bacterial
MeSH terms: Bacterial Infections; Renal Insufficiency
Intervention: Gepotidacin
Intervention description: Gepotidacin after reconstitution is a clear, dark brown to dark brownish-yellow solution, free from visible particulate matter. Subjects will receive gepotidacin 750 mg single IV dose over 2 hours.
Intervention MeSH terms: Gepotidacin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Normal Renal Function; end stage renal disease (ESRD); Pharmacokinetics; Gepotidacin; Renal Impairment

Summary:

      This study will be conducted to determine if altered renal function affects the plasma
      pharmacokinetics of gepotidacin, which will inform if dosing recommendations based upon renal
      impairment are required. The objective of this study is to compare the pharmacokinetics of
      gepotidacin administered as a 750 milligram (mg) intravenous (IV) dose in normal healthy
      subjects compared with subjects with mild, moderate, and severe renal impairment, and with
      subjects with end stage renal disease (ESRD). This is a Phase I, nonrandomized, open-label,
      parallel-group, multi-center, multi-part study. In Part 1, up to 16 subjects with normal
      renal function will be matched to approximately 8 subjects with moderate renal impairment,
      and approximately 8 subjects with severe renal impairment and/or subjects with ESRD not on
      hemodialysis for a total of approximately 32 subjects. In Part 2 (optional), approximately 4
      to 8 subjects with normal renal function (if enrolled), approximately 4 to 8 subjects with
      mild renal impairment, and approximately 4 to 8 subjects with ESRD on hemodialysis will be
      enrolled for a total of approximately 12 to 24 subjects. The duration from Screening to the
      Follow-up Visit will be approximately 44 days for Part 1 and approximately 50 days for Part
      2.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age: Male or female subject between 18 and 80 years of age, inclusive.

          -  Healthy subject 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. Subject with renal impairment must have clinical laboratory
             values consistent with their disease and are approved by the investigator.

          -  Subject with renal impairment (mild, moderate, severe, or subjects with ESRD) may be
             taking medications, which in the opinion of the investigator, are believed to be
             therapeutic but do not affect study drug absorption, distribution, metabolism, or
             excretion. These medications must be stable doses taken for at least 7 days before the
             first dose of study drug.

          -  Subject with normal renal function or renal impairment (estimated Glomerular
             Filtration Rate [eGFR] corresponding to the calculated eGFR [the estimated eGFR may be
             rounded to the nearest integer]) at Screening.

          -  Subjects with ESRD on hemodialysis should be on hemodialysis for at least 3 months
             before Screening and is able to tolerate a hemodialysis treatment lasting 3 to 4 hours
             with blood flow rates of >200 milliliter (mL)/minute (min).

          -  Alanine aminotransferase (ALT) and bilirubin <1.5 × upper limit of normal (ULN;
             isolated bilirubin >1.5 × ULN is acceptable, if bilirubin is fractionated and direct
             bilirubin <35%).

          -  Body weight >=50 kilograms (kg) and body mass index (BMI) within the range 18.5 and 40
             kg/square meter (m^2), inclusive.

          -  Male or Female. A female subject is eligible to participate if she is not pregnant (as
             confirmed by a negative serum human chorionic gonadotrophin test), not lactating, and
             at least one of the following conditions applies:

        Nonreproductive potential defined as:

          -  Premenopausal females with one of the following: Documented tubal ligation, Documented
             hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal
             occlusion, Hysterectomy, or Documented bilateral oophorectomy

          -  Postmenopausal defined as 12 months of continuous spontaneous amenorrhea (in
             questionable cases a blood sample will be obtained to test for simultaneous
             follicle-stimulating hormone) and estradiol levels consistent with menopause. Females
             on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be
             required to use one of the highly effective contraception methods if they wish to
             continue their HRT during the study. Otherwise, they must discontinue HRT to allow
             confirmation of post-menopausal status prior to study enrollment.

        Reproductive potential and agrees to follow 1 of the options listed in the GSK Modified
        List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive
        Potential requirements from 30 days prior to the first dose until completion of the
        Follow-up Visit.

        For subjects with indeterminate pregnancy test results or a persistently low human
        chorionic gonadotropin results, nonpregnancy status must be documented by other means
        (subjects with ESRD only).

          -  Capable of giving signed informed consent as described in protocol, which includes
             compliance with the requirements and restrictions listed in the consent form and in
             the protocol.

        Exclusion Criteria:

          -  Subject has a clinically significant abnormality in past medical history or at the
             Screening physical examination (excluding renal insufficiency and other related stable
             medical conditions within the renally impaired population of subjects [e.g.,
             hypertension, diabetes, or anemia, which should be stable for at least 3 months before
             the first dose of study drug]) 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 cardiac, hepatic, neurologic, gastrointestinal
             (GI), 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.

          -  Subject has a functioning renal transplant.

          -  Subject with renal impairment has a systolic blood pressure outside the range of 90 to
             200 millimeter of mercury (mm Hg), a diastolic blood pressure outside the range of 45
             to 110 mm Hg, or a heart rate outside the range of 40 to 120 beats per minute (bpm).

          -  Subject with renal impairment has a hemoglobin value <9 grams (g)/decilitre (dL).

          -  Female subject has a positive pregnancy test result or is lactating at Screening or
             upon admission to the clinic.

          -  Use of a systemic antibiotic within 30 days of Screening

          -  Within 2 months before Screening, either a confirmed history of Clostridium difficile
             diarrhoea infection or a past positive Clostridium difficile toxin test.

          -  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 renal impairment, 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 GlaxoSmithKline
             (GSK) medical monitor, contraindicates their participation.

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic
             uses heparin to maintain IV cannula patency).

          -  Subject has used medications known to affect the elimination of serum creatinine
             (e.g., trimethoprim or cimetidine) or competitors of renal tubular secretion (e.g.,
             probenecid) within 30 days before dosing.

          -  Subjects cannot use any over-the-counter, or prescription medication (except for
             hormonal contraceptives and/or acetaminophen), vitamin supplement, or herbal
             medication within 7 days (or 5 half-lives, whichever is longer) before dosing and
             during the study within 7 days before dosing and during the study.

          -  Subjects with normal renal function have a presence of hepatitis B surface antigen or
             positive hepatitis C antibody test result at Screening or within 3 months prior to
             first dose of study treatment. A subject with renal impairment with stable hepatitis C
             who has normal liver function test results is allowed with investigator approval.

          -  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 (and Day 7 for Group F only),
             other than those associated with underlying renal conditions or other stable medical
             conditions consistent with the disease process.

          -  Subject with normal renal function has a baseline corrected QT interval using the
             Fridericia formula (QTcF) of >450 milliseconds (msec) and subject with renal
             impairment has a baseline QTcF of >480 msec.

          -  Donation of blood in excess of 500 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.

          -  Previous exposure to gepotidacin within 12 months prior to the first dosing day.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day 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 is unable to comply with all study procedures, in the opinion of the
             investigator.

          -  The subject should not participate in the study, in the opinion of the investigator or
             Sponsor.