To Assess Bioavailability, Food Effect and Pharmacokinetics of Gepotidacin Tablets: A Phase I, Single-Dose, 2 Part Study in Healthy Subjects.
Condition: Infections, Bacterial
MeSH terms: Bacterial Infections
Intervention: Gepotidacin RC Tablet; Gepotidacin HSWG Tablet; Gepotidacin Capsule
Intervention description: The tablet is a capsule shape white film coated tablet with no identifying markings. This is an immediate release tablet containing gepotidacin 750 mg (free base) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing tablets.; The tablet is an oval shape white film coated tablet with no identifying markings. This is an immediate release tablets containing gepotidacin 750 mg (free base) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing tablets.; It is a pink gelatin size 00 capsule with no identifying markings containing slightly agglomerated pale yellow to grayish yellow to yellowish gray powder. This is an immediate release capsules containing gepotidacin 500 mg (mesylate salt) and inactive formulation excipients administered orally with 240 mL of water. Up to an additional 100 mL of water may be given to assist in swallowing capsules.
Intervention MeSH terms: Gepotidacin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Cross-over; Gepotidacin; Pharmacokinetics; Relative Bioavailability; non-compartmental PK analysis; High shear wet granulation

Summary:

      This study is divided in 2 parts. Part 1a is being conducted to evaluate the safety,
      tolerability, and relative bioavailability of the 2 free base tablet formulations (roller
      compacted [RC] and high shear wet granulation [HSWG]) compared to the reference capsule
      formulation under fasted conditions. This is a 3-period; cross-over study that will guide
      which gepotidacin formulation will be used for future studies. Following review of
      pharmacokinetic (PK) and safety data in Part 1a, a decision will be made whether to proceed
      with Parts 1b and 2.

      Part 1b is a 2-period, cross-over study and will assess the effect of food on the PK of the
      selected gepotidacin tablet formulation from Part 1a. In Part 2, the PK of the selected
      gepotidacin tablet formulation from Part 1a in Japanese (2a) and Chinese (2b) subjects will
      be evaluated under fasted conditions.

      The duration of the study (from Screening to the Follow-up visit) will be approximately 44
      days (Part 1a), 41 days (Part 1b) and 38 days (Part 2a and 2b each), respectively. The
      approximate number of subjects enrolled in Part 1a will be 27 (9 subjects in each of the 3
      treatment sequences), 16 in Part 1b (8 subjects in each of the 2 treatment sequences) and 12
      Japanese and 12 Chinese subjects in Part 2a and 2b, respectively.
    

Eligibility criteria:

        Inclusion Criteria

          -  Male or female subjects between 18 and 64 years of age inclusive, at the time of
             signing the informed consent.

          -  Healthy 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. A subject with a
             clinical abnormality or laboratory parameters outside the reference range for the
             population being studied may be included only if the investigator feels and documents
             that the finding is unlikely to introduce additional risk factors and will not
             interfere with the study procedures.

          -  Additional inclusion criteria for Japanese subjects (Part 2a only): the subject was a
             non-naturalized Japanese citizen and held a Japanese passport, the subject had 2
             Japanese parents and 4 Japanese grandparents who were all non naturalized Japanese
             citizens, as confirmed by interview and the subject had been living outside of Japan
             for up to 10 years as confirmed by interview.

          -  Additional inclusion criteria for Chinese subjects (Part 2b only): the subject was a
             non-naturalized Chinese citizen and held a Chinese passport, the subject had 2 Chinese
             parents and 4 Chinese grandparents who were all non naturalized Chinese citizens, as
             confirmed by interview, the subject had been living outside of China for up to 10
             years as confirmed by interview.

          -  Body weight for subjects in Part 1a and 1b: more than equal to (>=) 50 kilogram (kg)
             and body mass index (BMI) within the range 19 and 32 kilogram per meter square
             (kg/m^2), inclusive and for Japanese and Chinese subjects (Part 2a and 2b): >=50 kg
             and BMI within the range 18 and 32 kg/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. Non-reproductive potential defined
             as: pre-menopausal females with one of the following: documented tubal ligation,
             documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
             bilateral tubal occlusion, hysterectomy, documented bilateral oophorectomy and
             postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a
             blood sample with 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 enrolment. Reproductive potential and agrees to follow one of the options listed
             in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of
             Reproductive Potential from 30 days prior to the first dose of study medication and
             until completion of the Follow-up visit.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

        Exclusion Criteria

          -  Subject has a clinically significant abnormality in past medical history or at the
             Screening physical examination 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, 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.

          -  QTc more than (>) 450 millisecond (msec).

          -  Use of a systemic antibiotic within 30 days of Screening.

          -  Within 2 months before Screening, either a confirmed history of Clostridium difficile
             diarrhea infection or a past positive Clostridium difficile toxin test.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic
             uses heparin to maintain intravenous cannula patency).

          -  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.

          -  History of regular alcohol consumption within 6 months of screening defined as an
             average weekly intake of >21 units (or an average daily intake of >3 units) for males
             or an average weekly intake of >14 units (or an average daily intake >2 units) for
             females. One unit is equivalent to 270 milliliter (mL) of full strength beer, 470 mL
             of light beer, 30 mL of spirits, or 100 mL of wine.

          -  Urinary cotinine level indicative of smoking or history or regular use of tobacco- or
             nicotine containing products within 3 months before screening.

          -  History of sensitivity to any of the study medications, or components thereof, or a
             history of drug or other allergy that, in the opinion of the investigator or medical
             monitor, contraindicates their participation.

          -  Presence of hepatitis B surface antigen, positive hepatitis C antibody test result at
             screening or within 3 months prior to first dose of study treatment.

          -  Female subject has a positive pregnancy test result or is lactating at Screening or
             upon admission to the clinic.

          -  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 less than [<] 35 percent [%]).

          -  Urinalysis positive for blood without other cause identified.

          -  A positive pre-study drug/alcohol screen.

          -  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.

          -  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.

          -  Exclusion criteria for screening and baseline 12-lead ECG (a single repeat is allowed
             for eligibility determination): male subjects with heart rate <40 and >100 beats per
             minute (bpm), female subjects with heart rate <50 and >100 bpm, PR interval <120 and
             >220 msec for male and female subjects, QRS duration <70 and >120 msec in both male
             and female subjects and corrected QT interval using Bazett's formula (QTcB) or
             corrected QT interval using Fridericia's formula (QTcF) >450 msec in both male and
             female subjects. Evidence of previous myocardial infarction (does not include ST
             segment changes associated with repolarization). Any conduction abnormality (including
             but not specific to left or right complete bundle branch block, atrioventricular block
             [second degree or higher], Wolf Parkinson White syndrome), sinus pauses >3 seconds,
             non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular
             ectopic beats) or any significant arrhythmia which, in the opinion of the principal
             investigator and GlaxoSmithKline medical monitor, will interfere with the safety of
             the individual subject.

          -  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.