Clinical trial NCT02729038: Pharmacokinetic Study of Gepotidacin in Subjects With Varying Degrees of Renal Impairment and in Subjects With Normal Renal Function
Official title: A Phase I, Open-Label, Single-Dose, Multi-Part Study to Assess the Pharmacokinetics of Gepotidacin (GSK2140944) in Male and Female Adult Subjects With Varying Degrees of Renal Impairment and in Matched Control Subjects With Normal Renal Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infections, Bacterial
Keywords: Normal Renal Function
end stage renal disease (ESRD)
Pharmacokinetics
Gepotidacin
Renal Impairment
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-04-06
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Area Under the Plasma Concentration Time Curve (AUC) From Hour 0 to Infinity (AUC[0-inf]) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: AUC (0-inf) of Gepotidacin for Part 2
timeFrame: 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.
measure: Maximum Observed Plasma Concentration (Cmax) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: Cmax of Gepotidacin for Part 2
timeFrame: 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.
measure: Total Amount Excreted in Urine (Ae Total), Part 1
timeFrame: 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
measure: Ae Total of Gepotidacin for Part 2
timeFrame: 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
measure: Percentage of the Given Dose Excreted in Urine (fe%) of Gepotidacin for Part 1
timeFrame: 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
measure: fe% of Gepotidacin for Part 2
timeFrame: 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
measure: Renal Clearance (CLr) of Gepotidacin for Part 1
timeFrame: 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
measure: CLr of Gepotidacin for Part 2
timeFrame: 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
measure: AUC (t0-t1) of Gepotidacin for Part 2
timeFrame: Dialysate fluid were to be collected on Day 1 after dosing (Period 1 only) at pre-dose from 0 to 4 hours
measure: Dialysis Clearance (CLD) of Gepotidacin for Part 2
timeFrame: Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1
measure: 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
timeFrame: 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:
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Readings for Part 1
timeFrame: Up to 16 Days
measure: Number of Participants With Abnormal 12-lead ECG Readings for Part 2
timeFrame: Up to 23 Days
measure: Change From Baseline in Vitals- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure, Part 1
timeFrame: Baseline and up to 16 Days
measure: Change From Baseline in Vitals- SBP and DBP, Part 2
timeFrame: Baseline and up to 23 Days
measure: Change From Baseline in Vitals- Pulse Rate, Part 1
timeFrame: Baseline and up to 16 Days
measure: Change From Baseline in Vitals- Pulse Rate, Part 2
timeFrame: Baseline and Up to 23 Days
measure: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) for Part 1
timeFrame: Up to 16 Days
measure: Number of Participants With Any AEs and Any SAEs for Part 2
timeFrame: Up to 23 Days
measure: Number of Participants With Clinical Laboratory Test Results for Grade 3 or Higher for Part 1
timeFrame: Up to 17 Days
measure: Number of Participants With Clinical Laboratory Test Results for Grade 3 or Higher for Part 2
timeFrame: Up to 24 Days
measure: Number of Participants With Abnormal Physical Examination Results for Part 1
timeFrame: Up to 16 Days
measure: Number of Participants With Abnormal Physical Examination Results for Part 2
timeFrame: Up to 23 Days
measure: AUC (0-t) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: AUC (0-t) of Gepotidacin for Part 2
timeFrame: Pre-dose, 0.25 , 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.
measure: Systemic Clearance (CL) of Gepotidacin for Part 1
timeFrame: At pre-dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, and 48 hours post-dose during the single treatment period.
measure: CL of Gepotidacin for Part 2
timeFrame: At pre-dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, and 48 hours post-dose in each of the two treatment periods
measure: Terminal Elimination Rate Constant (lambda_z) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: Lambda_z of Gepotidacin for Part 2
timeFrame: 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
measure: Terminal Phase Half-life (t1/2) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: t1/2 of Gepotidacin for Part 2
timeFrame: Pre-dose, 0.25 , 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.
measure: Time to Maximum Plasma Concentration (Tmax) of Gepotidacin for Part1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: Tmax of Gepotidacin for Part 2
timeFrame: Pre-dose, 0.25 , 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.
measure: Volume of Distribution at Steady State of Parent Drug (Vss) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: Vss of Gepotidacin for Part 2
timeFrame: Pre-dose, 0.25 , 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.
measure: Volume of Distribution of the Terminal Phase (Vz) of Gepotidacin for Part 1
timeFrame: Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
measure: Vz of Gepotidacin for Part 2
timeFrame: Pre-dose, 0.25 , 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.
measure: Cumulative Amount of Drug Excreted in Urine From Time t1 to t2 (Ae[t1-t2]) of Gepotidacin for Part 1, for Normal
timeFrame: At Pre-dose, 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
measure: Cumulative Amount of Drug Excreted in Urine From Time t1 to t2 (Ae[t1-t2]) of Gepotidacin for Part 1, for Moderate and Severe
timeFrame: at pre-dose (0.0), 0 to 6 hours, 6 to 12 hours, 12 to 24 hours, 24 to 36, and 36 to 48 hours post-dose during the single treatment period
measure: Ae(t1-t2) of Gepotidacin for Part 2
timeFrame: 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
measure: Total Amount of Unchanged Amount of Drug Removed by Hemodialysis (Arem) From Time 0 to 1 Hour After the Start of Hemodialysis (Arem[0-1]), Arem (1-2), Arem (2-3), Arem (3-4) for Part 2
timeFrame: Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1Dialysate fluid were collected at 1, 2, 3, and 4 hours post-dose in Period 1 only
Other outcomes:
Locations:
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.