Pharmacokinetic Study of Gepotidacin in Subjects With Varying Degrees of Renal Impairment and in Subjects With Normal Renal Function

NCT02729038 | Completed Phase 1 Results

• 1 other identifier: 116849
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Infections, Bacterial

Keywords

Normal Renal Function; end stage renal disease (ESRD); Pharmacokinetics; Gepotidacin; Renal Impairment

Outcome Measures

Primary Outcomes (13)

• Area Under the Plasma Concentration Time Curve (AUC) From Hour 0 to Infinity (AUC[0-inf]) of Gepotidacin for Part 1

  AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity . Blood samples were collected at the indicated time-points, during the study. The Pharmacokinetic (PK) Parameter Population consisted of all participants in the PK Population, for whom valid and evaluable PK parameters were derived. The PK Population consisted of all participant's, who received at least 1 dose of gepotidacin and had evaluable PK data.

  Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.

• AUC (0-inf) of Gepotidacin for Part 2

  AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for gepotidacin. Blood samples were collected at the indicated time-points, during the study.

  Pre-dose, 0.25 hours, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose during treatment period 1 and 2 both.

• Maximum Observed Plasma Concentration (Cmax) of Gepotidacin for Part 1

  Cmax, is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected, at the indicated time points for analysis of gepotidacin.

  Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.

• Cmax of Gepotidacin for Part 2

  Cmax, is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected, at the indicated time points for analysis of gepotidacin.

  Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose on during treatment period 1 and 2 both.

• Total Amount Excreted in Urine (Ae Total), Part 1

  Urine samples from the participants were collected during the study. Ae total assessed the, total unchanged drug (total amount of drug excreted in urine), which was calculated, by adding all the fractions of drug gepotidacin collected, at the indicated time points. No formal statistical analysis of group comparison was planned for urine PK parameters.

  Pre-dose (0.0), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during the single treatment period

• Ae Total of Gepotidacin for Part 2

  Urine samples, from the participants were collected during the study. Ae total assessed the, total unchanged drug (total amount of drug excreted in urine), which was calculated, by adding all the fractions of drug gepotidacin collected, at the indicated time points. Urine samples were collected at pre-dose (0.0), 0 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during the single treatment period. Only those participant's available at the specified time points were analyzed. No formal statistical analysis of group comparison was planned for urine PK parameters.

  Pre-dose (0.0), 0 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during both treatment period 1 and 2

• Percentage of the Given Dose Excreted in Urine (fe%) of Gepotidacin for Part 1

  The fe% measured the percentage of the given dose of drug gepotidacin, excreted in urine. It was calculated as: Ae total divided by the dose administered multiplied by 100.

  At pre-dose (0.0), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during the single treatment period

• fe% of Gepotidacin for Part 2

  The fe% measured the percentage of the given dose of drug gepotidacin, excreted in urine. It was calculated as: Ae total divided by the dose administered multiplied by 100. No formal statistical analysis of group comparison was planned for urine PK parameters. Only those participants available at the specified time points were analyzed.

  At pre-dose (0.0), 0 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose in each of the two treatment periods

• Renal Clearance (CLr) of Gepotidacin for Part 1

  Renal clearance is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time via renal clearance pathways, expressed as volume (Liter) per unit of time (hour). The renal clearance was calculated by Ae total divided by AUC from hour 0 to the last measurable plasma concentration AUC (0-t). Urine samples were collected at pre-dose (0.0), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during the single treatment period. No formal statistical analysis of group comparison was planned for urine PK parameters.

  At pre-dose (0.0), 0 to 2 hours, 2 to 4 hours, 4 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose during the single treatment period

• CLr of Gepotidacin for Part 2

  Renal clearance is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time via renal clearance pathways, expressed as volume (Liter) per unit of time (hour). Urine samples were collected at pre-dose (0.0), 0 to 6 hours, 6 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose in each of the two treatment periods. Only those participant's available at the specified time points were analyzed. No formal statistical analysis of group comparison was planned for urine PK parameters.

  At pre-dose (0.0), 0 to 8 hours, 8 to 12 hours, 12 to 24 hours, 24 to 36 hours, and 36 to 48 hours post-dose in each of the two treatment periods

• AUC (t0-t1) of Gepotidacin for Part 2

  Partial area under the curve estimated from predialyzer samples collected from start of dialysis (t0) to end of dialysis (t1). Only applicable to Part 2 ESRD on hemodialysis (before hemodialysis) arm..

  Dialysate fluid were to be collected on Day 1 after dosing (Period 1 only) at pre-dose from 0 to 4 hours

• Dialysis Clearance (CLD) of Gepotidacin for Part 2

  CLD measured the dialysis clearance of gepotidacin over the specified duration in the study and indicates how quickly gepotidacin is cleared out from blood or plasma. Only applicable to Part 2 ESRD on hemodialysis (before hemodialysis) arm.

  Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1

• Fraction (%) of the Dose Removed by Hemodialysis From 0 to 4 Hours After the Start of Hemodialysis (Frem%[0-4]) of Gepotidacin for Part 2

  Dialysate samples were collected at specified time points in the study. Frem is defined as the fraction (dose in percentage) removed by the process of hemodialysis from 0 to 4 hours after the start of hemodialysis (or to the end of dialysis if less than 4 hours)

  Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1

Secondary Outcomes (30)

• Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Readings for Part 1

  Up to 16 Days

• Number of Participants With Abnormal 12-lead ECG Readings for Part 2

  Up to 23 Days

• Change From Baseline in Vitals- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure, Part 1

  Baseline and up to 16 Days

• Change From Baseline in Vitals- SBP and DBP, Part 2

  Baseline and up to 23 Days

• Change From Baseline in Vitals- Pulse Rate, Part 1

  Baseline and up to 16 Days

Study Arms (6)

Part 1: Subjects with normal renal function (Group A)

EXPERIMENTAL

Subjects with normal renal function will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.

Drug: Gepotidacin

Part 1: subjects with moderate renal impairment (Group B)

EXPERIMENTAL

Subjects with moderate renal impairment will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.

Drug: Gepotidacin

Part 1: subjects with severe renal impairment (Group C)

EXPERIMENTAL

Subjects with severe renal impairment and subjects with ESRD not on hemodialysis will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.

Drug: Gepotidacin

Part 2: subjects with normal renal function (Group D)

EXPERIMENTAL

Subjects with normal renal function will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.

Drug: Gepotidacin

Part 2: subjects with mild renal impairment (Group E)

EXPERIMENTAL

Subjects with mild renal impairment will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.

Drug: Gepotidacin

Part 2: subjects with ESRD on hemodialysis (Group F)

EXPERIMENTAL

Subjects with ESRD on hemodialysis will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion starting approximately 2 hours before the initiation of the last hemodialysis session of the week (Period 1) and gepotidacin 750 mg administered as a 2 hour IV infusion starting within 2 hours after completion of the last hemodialysis session of the week (Period 2).

Drug: Gepotidacin

Interventions

Gepotidacin DRUG

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.

Part 1: Subjects with normal renal function (Group A); Part 1: subjects with moderate renal impairment (Group B); Part 1: subjects with severe renal impairment (Group C); Part 2: subjects with ESRD on hemodialysis (Group F); Part 2: subjects with mild renal impairment (Group E); Part 2: subjects with normal renal function (Group D)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

Miami, Florida, 33136, United States

Location

GSK Investigational Site

Orlando, Florida, 32809, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Hossain M, Tiffany C, Raychaudhuri A, Nguyen D, Tai G, Alcorn H Jr, Preston RA, Marbury T, Dumont E. Pharmacokinetics of Gepotidacin in Renal Impairment. Clin Pharmacol Drug Dev. 2020 Jul;9(5):560-572. doi: 10.1002/cpdd.807. Epub 2020 May 19.

  PMID: 32429000 BACKGROUND

MeSH Terms

Conditions

Bacterial Infections; Kidney Failure, Chronic; Renal Insufficiency

Interventions

gepotidacin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections; Renal Insufficiency, Chronic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: March 31, 2016
• First Posted: April 6, 2016
• Study Start: June 29, 2016
• Primary Completion: June 20, 2017
• Study Completion: June 20, 2017
• Last Updated: July 21, 2020
• Results First Posted: November 20, 2018

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (3)