Relative Bioavailability, Safety, Tolerability, Pharmacokinetics (PK) and Food Effect Study of GSK2140944 in Healthy Subjects

NCT02045849 | Completed Phase 1

• 1 other identifier: 117349
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

This study will be conducted in three parts (Part 1, Part 2 and Part 3). Part 1 of this study will evaluate the relative bioavailability of a single dose of GSK2140944 tablet formulation compared to the reference capsule formulation under fasted conditions. The effect of food on the pharmacokinetics (PK) of a single dose of the tablet formulation will also be assessed. Part 2 will evaluate the effect of repeat doses of itraconazole on the pharmacokinetics of GSK2140944 following a single dose. A decision will be made whether to use the current capsule formulation or the new tablet formulation in Part 2 based upon the safety and PK data obtained from Part 1. Part 3 is conditionally based upon progression of the tablet formulation from Part 1 and will evaluate the effect of food on the safety, tolerability, and pharmacokinetics of the tablet formulation following multiple doses in elderly healthy subjects.

Conditions

Infections, Bacterial

Keywords

pharmacokinetics; GSK2140944; tolerability; drug interaction; safety; itraconazole; elderly healthy subjects; food effect; relative bioavailability

Outcome Measures

Primary Outcomes (7)

• Part 1: Composite of PK parameters following GSK2140944 administration in fasted and fed state

  PK parameters will include area under the concentration-time curve (AUC) from time zero (pre-dose) extrapolated to infinite time AUC(0-infinity), AUC from time zero to last quantifiable concentration AUC(0-t), relative bioavailability of drug (Frel), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), lag time before observation of drug concentration (tlag) and terminal phase half-life (t1/2) in the fasted state; AUC(0-infinity), AUC(0-t), tmax, tlag and Cmax after moderate fat meal.

  Day 1 (Pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, and at 48h)

• Part 2: Composite of PK parameters of GSK2140944 following repeat oral dosing of itraconazole

  PK parameters will include AUC(0-infinity), AUC(0-t), tmax, tlag and Cmax of GSK2140944.

  Day 1 and Day 7 (Predose, 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h post dose and also at 60h and 72h post dose on Day 7

• Part 3: Safety and tolerability of GSK2140944 as assessed by adverse events (AEs)

  Approximately 8 weeks

• Part 3: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications

  Approximately 8 weeks

• Part 3: Safety and tolerability of GSK2140944 by laboratory assessments

  Laboratory assessments will include hematology, clinical chemistry, urinalysis parameters

  Approximately 8 weeks

• Part 3: Safety and tolerability of GSK2140944 as assessed by 12-lead electrocardiograms (ECGs)

  All 12-lead ECGs will be obtained after the subject has rested in a supine position for at least 10 minutes

  Approximately 8 weeks

• Part 3: Safety and tolerability of GSK2140944 as assessed by vital signs

  Vital signs will be measured for subjects in supine position and will include systolic and diastolic blood pressure, pulse rate and temperature

  Approximately 8 weeks

Secondary Outcomes (10)

• Part 1: Safety and tolerability of GSK2140944 as assessed by AEs

  Approximately 7 weeks

• Part 1: Safety and tolerability of GSK2140944 as assessed by review of concomitant medications

  Approximately 7 weeks

• Part 1: Safety and tolerability of GSK2140944 by laboratory assessments

  Approximately 7 weeks

• Part 1: Safety and tolerability of GSK2140944 as assessed by 12-lead ECGs

  Approximately 7 weeks

• Part 1: Safety and tolerability of GSK2140944 as assessed by vital signs

  Approximately 7 weeks

Study Arms (3)

Part 1

EXPERIMENTAL

Subjects will receive either GSK2140944 1500 mg (500 mg x 3) capsules under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fasted conditions or GSK2140944 1500 mg (750 mg x 2) tablets under fed conditions as per the randomization schedule in each of the three periods with a washout period of at least 3 days between the doses. There will also be a follow-up visit within 5-7 days after the last dose of study drug.

Drug: GSK2140944 capsule; Drug: GSK2140944 tablet

Part 2

EXPERIMENTAL

Subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) on Day 1 followed by a repeat dose of Itraconazole 200 mg once daily for 6 days from Day 4 to Day 9. On Day 7, subjects will receive a single dose of GSK2140944 1500 mg (tablet or capsule) one hour after the dose of Itraconazole. There will also be a follow-up visit within 5-7 days after the last dose of study drug.

Drug: GSK2140944 capsule; Drug: GSK2140944 tablet; Drug: Itraconazole capsule

Part 3

EXPERIMENTAL

Subjects in Group 1 will receive GSK2140944 1500 mg (750 mg x 2) tablets twice daily from Day 1 to Day 5 under fasting and fed conditions in Period I and Period II, respectively. Subjects in Group 2 will receive GSK2140944 1500 mg (750 mg x 2) tablets twice daily from Day 1 to Day 5 under fed and fasting conditions in Period I and Period II, respectively. There will be a washout of at least 7 days between the periods. Subjects will have a follow up visit 5-7 days after the last dose of study drug in both the groups.

Drug: GSK2140944 tablet

Interventions

GSK2140944 capsule DRUG

Immediate release capsule containing GSK2140944 and inactive formulation excipients with a unit dose strength of 500 mg

Part 1; Part 2

GSK2140944 tablet DRUG

Immediate release tablet containing GSK2140944 and inactive formulation excipients with a unit dose strength of 750 mg

Part 1; Part 2; Part 3

Itraconazole capsule DRUG

Capsule containing Itraconazole with a unit dose strength of 100 mg

Part 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. 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.
• Part 1 and 2: Male or female between 18 and 64 years of age inclusive, at the time of signing the informed consent. Part 3: Male or female subjects at least 65 years of age or older at the time of signing the informed consent.
• A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. To confirm post-menopausal status, a blood sample for simultaneous follicle stimulating hormone (FSH) \>40 milli-International Units (MIU)/milliliter (mL) and estradiol \<40 picograms (pg)/mL (\<147 picomoles \[pmol\]/liter \[L\]) is confirmatory. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the final follow-up visit.
• Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 19 - 31 kg/meter square (m\^2) (inclusive).
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Alanine amino transferase (ALT), alkaline phosphatase and bilirubin \<=1.5xUpper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

You may not qualify if:

• Criteria Based Upon Medical Histories
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Any clinically significant central nervous system (e.g., seizures), cardiac, pulmonary, metabolic, renal, hepatic or gastrointestinal conditions or history of such conditions that, in the opinion of the investigator may place the subject at an unacceptable risk as a participant in this trial or may interfere with the absorption, distribution, metabolism or excretion of drugs.
• History of photosensitivity to quinolones.
• Use of systemic antibiotic within 30 days of screening
• Previous exposure to GSK2140944
• Confirmed history of C-difficile diarrhea.
• History of tendon rupture.
• History of drug abuse within 6 months of the study.
• History of smoking or use of nicotine containing products within 3 months of screening, or a positive urine cotinine indicative of smoking at screening.
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• 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 GSK Medical Monitor, contraindicates their participation.
• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinical research unit uses heparin to maintain intravenous cannula patency).
• Criteria Based Upon Diagnostic Assessments
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or positive Human Immunodeficiency Virus (HIV) antibody.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Tiffany C, Dumont EF, Hossain M, Srinivasan M, Swift B. Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects. Clin Transl Sci. 2022 Sep;15(9):2251-2264. doi: 10.1111/cts.13359. Epub 2022 Jul 13.

  PMID: 35769034 DERIVED

Related Links

• Results for study 117349 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Bacterial Infections

Interventions

gepotidacin; Itraconazole

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2014
• First Posted: January 27, 2014
• Study Start: January 28, 2014
• Primary Completion: August 21, 2014
• Study Completion: August 21, 2014
• Last Updated: July 13, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will share

Locations

US (1)