To Assess Bioavailability, Food Effect and Pharmacokinetics of Gepotidacin Tablets: A Phase I, Single-Dose, 2 Part Study in Healthy Subjects.

GlaxoSmithKline (GSK)

Status and phase

Completed

Phase 1

Conditions

Infections, Bacterial

Treatments

Drug: Gepotidacin HSWG Tablet

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin Capsule

Study type

Interventional

Funder types

Industry

Identifiers

NCT02853435

117351

Details and patient eligibility

About

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.

Enrollment

48 patients

Sex

All

Ages

18 to 64 years old

Volunteers

Accepts Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Crossover Assignment

Masking

None (Open label)

48 participants in 7 patient groups

Part1a: Gepotidacin 1500 mg-Sequence A-capsules, B-RC, C-HSWG

Experimental group

Description:

Subjects will be receive treatment sequence (ABC) which is a single dose of gepotidacin 1500 mg (three tablets of 500 mg) reference capsule (Treatment A) in Period 1, 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in Period 2 or 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 3, according to randomization. There will be a washout period of at least 3 days between doses.

Treatment:

Drug: Gepotidacin Capsule

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part1a: Gepotidacin 1500 mg-Sequence C-HSWG, A-capsules, B-RC)

Experimental group

Description:

Subjects will receive treatment sequence (CAB) to receive a single dose of gepotidacin 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 1, 1500 mg (three tablets of 500 mg) reference capsule (Treatment A) in Period 2 or 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in Period 3 according to randomization. There will be a washout period of at least 3 days between doses.

Treatment:

Drug: Gepotidacin Capsule

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part1a: Gepotidacin 1500 mg-Sequence B-RC, C-HSWG, A-capsules)

Experimental group

Description:

Subjects will receive treatment sequence (BCA) to receive a single dose of gepotidacin 1500 mg (two tablets of 750 mg) RC tablet (Treatment B) in period 1, 1500 mg (two tablets of 750 mg) HSWG tablet (Treatment C) in Period 2, or 1500 mg (three tablets of 500 mg) (Treatment A) in Period 3 reference capsule according to randomization.. There will be a washout period of at least 3 days between doses.

Treatment:

Drug: Gepotidacin Capsule

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part1b: Gepotidacin 1500 mg-Sequence DE-fasted followed by fed

Experimental group

Description:

Subjects will receive treatment sequence (DE) according to randomization which is a single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a under fasted condition (Treatment D) in Period 1 followed by fed conditions (Treatment E) in period 2. There will be a washout period of at least 3 days between doses.

Treatment:

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part1b: Gepotidacin 1500 mg-Sequence ED-fed followed by fasted

Experimental group

Description:

Subjects will be receive treatment sequence (ED) according to randomization which is single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a under fed condition (Treatment E) in period 1 followed by fasted conditions (Treatment D) in Period 2. There will be a washout period of at least 3 days between doses.

Treatment:

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part 2a: Gepotidacin 1500 mg (RC or HSWG)- Japanese subjects

Experimental group

Description:

Japanese subjects will receive a single 1500 mg (two tablets of 750 mg) dose of gepotidacin tablet (RC or HSWG) selected from Part 1a.

Treatment:

Drug: Gepotidacin RC Tablet

Drug: Gepotidacin HSWG Tablet

Part 2b: Gepotidacin 1500 mg (RC or HSWG)- Chinese subjects

Experimental group