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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- Cmax of Gepotidacin for Part 2
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Part 1: Subjects with normal renal function (Group A)
Subjects with normal renal function will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.
干预措施: Gepotidacin (Drug)
Part 1: subjects with moderate renal impairment (Group B)
Subjects with moderate renal impairment will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.
干预措施: Gepotidacin (Drug)
Part 1: subjects with severe renal impairment (Group C)
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.
干预措施: Gepotidacin (Drug)
Part 2: subjects with normal renal function (Group D)
Subjects with normal renal function will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.
干预措施: Gepotidacin (Drug)
Part 2: subjects with mild renal impairment (Group E)
Subjects with mild renal impairment will receive a single dose of gepotidacin 750 mg administered as a 2 hour IV infusion.
干预措施: Gepotidacin (Drug)
Part 2: subjects with ESRD on hemodialysis (Group F)
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).
干预措施: Gepotidacin (Drug)
结局指标
主要结局
Cmax of Gepotidacin for Part 2
时间窗: 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.
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.
Maximum Observed Plasma Concentration (Cmax) of Gepotidacin for Part 1
时间窗: 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, 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.
Total Amount Excreted in Urine (Ae Total), Part 1
时间窗: 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
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.
Ae Total of Gepotidacin for Part 2
时间窗: 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
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.
fe% of Gepotidacin for Part 2
时间窗: 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
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.
Renal Clearance (CLr) of Gepotidacin for Part 1
时间窗: 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
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.
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
时间窗: Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1
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)
Area Under the Plasma Concentration Time Curve (AUC) From Hour 0 to Infinity (AUC[0-inf]) of Gepotidacin for Part 1
时间窗: 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), 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.
AUC (0-inf) of Gepotidacin for Part 2
时间窗: 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.
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.
Percentage of the Given Dose Excreted in Urine (fe%) of Gepotidacin for Part 1
时间窗: 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
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.
AUC (t0-t1) of Gepotidacin for Part 2
时间窗: Dialysate fluid were to be collected on Day 1 after dosing (Period 1 only) at pre-dose from 0 to 4 hours
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..
CLr of Gepotidacin for Part 2
时间窗: 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 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.
Dialysis Clearance (CLD) of Gepotidacin for Part 2
时间窗: Pre-dose, 0-1 hours, 1-2 hours, 2-3 hours and 3-4 hours post-dose on Day 1 in Period 1
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.
次要结局
- Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Readings for Part 1(Up to 16 Days)
- Change From Baseline in Vitals- Pulse Rate, Part 1(Baseline and up to 16 Days)
- t1/2 of Gepotidacin for Part 2(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.)
- Volume of Distribution at Steady State of Parent Drug (Vss) of Gepotidacin for Part 1(Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.)
- Cumulative Amount of Drug Excreted in Urine From Time t1 to t2 (Ae[t1-t2]) of Gepotidacin for Part 1, for Normal(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)
- AUC (0-t) of Gepotidacin for Part 1(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-t) of Gepotidacin for Part 2(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.)
- Tmax of Gepotidacin for Part 2(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.)
- Number of Participants With Abnormal 12-lead ECG Readings for Part 2(Up to 23 Days)
- Number of Participants With Clinical Laboratory Test Results for Grade 3 or Higher for Part 2(Up to 24 Days)
- Number of Participants With Abnormal Physical Examination Results for Part 2(Up to 23 Days)
- Terminal Elimination Rate Constant (lambda_z) of Gepotidacin for Part 1(Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.)
- Lambda_z of Gepotidacin for Part 2(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)
- 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- Pulse Rate, Part 2(Baseline and Up to 23 Days)
- Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) for Part 1(Up to 16 Days)
- Number of Participants With Clinical Laboratory Test Results for Grade 3 or Higher for Part 1(Up to 17 Days)
- Number of Participants With Abnormal Physical Examination Results for Part 1(Up to 16 Days)
- Systemic Clearance (CL) of Gepotidacin for Part 1(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.)
- Vss of Gepotidacin for Part 2(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.)
- Change From Baseline in Vitals- SBP and DBP, Part 2(Baseline and up to 23 Days)
- Number of Participants With Any AEs and Any SAEs for Part 2(Up to 23 Days)
- CL of Gepotidacin for Part 2(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)
- Volume of Distribution of the Terminal Phase (Vz) of Gepotidacin for Part 1(Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.)
- Terminal Phase Half-life (t1/2) of Gepotidacin for Part 1(Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.)
- Time to Maximum Plasma Concentration (Tmax) of Gepotidacin for Part1(Pre-dose, 0.25 , 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.)
- 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(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)
- Vz of Gepotidacin for Part 2(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.)
- Cumulative Amount of Drug Excreted in Urine From Time t1 to t2 (Ae[t1-t2]) of Gepotidacin for Part 1, for Moderate and Severe(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)
- Ae(t1-t2) of Gepotidacin for Part 2(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)