Pharmacokinetics (PK) Study of Gepotidacin (GSK2140944) in Adult Subjects With Varying Degrees of Hepatic Impairment and in Matched Control Subjects With Normal Hepatic Function

Infections, Bacterial Clinical Trial

Official title:

A Phase I, Open-Label, Single-Dose, Two-Part Study to Assess the Pharmacokinetics of Gepotidacin (GSK2140944) in Male and Female Adult Participants With Varying Degrees of Hepatic Impairment and in Matched Control Participants With Normal Hepatic Function

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03562117
• Other study ID #: 117352
• Status: Completed
• Phase: Phase 1
• Start date: June 14, 2018
• Est. completion date: December 26, 2018

Study information

• Verified date: March 2021
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a two-part study which will evaluate the PK, safety, and tolerability of a single 1500 milligram (mg) oral dose of gepotidacin in subjects with normal hepatic function and in subjects with mild, moderate, and severe hepatic impairment. In Part 1, subjects with moderate hepatic impairment and subjects with normal hepatic function will be enrolled. Matching subjects with normal hepatic function in Part 1 (Group D), will be enrolled following the completion of all Day 3 assessments of the respective matched, hepatically impaired subject. In Part 2, subjects with mild (optional) and severe hepatic impairment and subjects with normal hepatic function will be enrolled concurrently based on the PK, safety, and tolerability data of Part 1. Subjects with mild hepatic impairment, may be studied if there is a significant difference in PK between subjects with moderate hepatic impairment and subjects with normal hepatic function. Subjects with severe hepatic impairment, will be studied in Part 2, provided that, the PK objectives are achieved in Part 1. A totals of 48 subjects, are planned to be enrolled in the study. The study duration is approximately of 44 days from Screening to Follow-up visit. The results from this study will enable the development of appropriate dosing recommendations in subjects with impaired hepatic function.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: December 26, 2018
• Est. primary completion date: December 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Subjects must be 18 to 80 years of age inclusive, at the time of signing the informed consent.

• Healthy subjects 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.

• Hepatically impaired subjects must have chronic (>6 months), stable (no acute episodes of illness within the previous 1 month prior to screening due to deterioration in hepatic function) hepatic insufficiency with features of cirrhosis due to any etiology. Subjects must also remain stable throughout the Screening period.

• Hepatically impaired subjects, will be classified, using the Child-Pugh classification system. Subjects must have, a Child-Pugh score, of 5 to 6 (mild hepatic impairment), 7 to 9 (moderate hepatic impairment), or 10 to 15 (severe hepatic impairment), with known medical history of liver disease (with or without a known history of alcohol abuse), and previous confirmation of liver cirrhosis by liver biopsy or other medical imaging technique (including laparoscopy, computed tomography scan, magnetic resonance imaging, or ultrasonography) associated with unambiguous medical history. If imaging study, or biopsy is not available, then the subject should have one of the following: Physical findings such as hepatomegaly, ascites, palmar erythema, spider angiomata, abdominal venous collaterals, gynecomastia, or other physical manifestations of hepatic disease Or Laboratory findings: ALT or AST elevation (> upper limit of normal [ULN]), alkaline phosphatase, or total bilirubin, or international normalized ratio (INR) elevation (>ULN) or an albumin value that is below the lower limit of normal laboratory reference range.

• Subjects with hepatic impairment may be taking medications, which in the opinion of the investigator, are believed to be therapeutic, and these medications should not interfere with the conduct of the study. Subjects with hepatic impairment should be on stable regimen of chronic medications for at least 7 days prior to dosing until completion of the Follow-Up Visit.

• Subjects with hepatic impairment must have platelet counts of 30,000 × 109/Liter of blood and have not had any major bleeding episodes within the past 6 months.

• Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 18.5 to 40 kg/meter^2 (inclusive).

• Male subjects must agree to use contraception, as protocol from Day -1 until completion of the Follow-up Visit or, female subject will be eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applied Not a woman of childbearing potential (WOCBP) or A WOCBP who agrees to follow the contraceptive guidance from 30 days prior to study drug administration and until completion of the Follow-up Visit.

• Capable of giving signed informed consent.

Exclusion Criteria:

• Subject has a clinically significant abnormality in past medical history or at the Screening physical examination (excluding hepatic insufficiency and other related medical conditions within the hepatically impaired populations, which should be stable for at least 1 month before study drug administration), 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 significant cardiac, 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.

• Female subject, has a positive pregnancy test result or is lactating at Screening or upon admission to the clinic.

• Subject has used a systemic antibiotic within 7 days of Screening.

• Subject has a confirmed history of Clostridium (C) difficile infection or a positive C. difficile toxin test, within 2 months before Screening.

• 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 hepatic impairment, and 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 GSK medical monitor, contraindicates their participation.

• History of sensitivity to heparin or heparin-induced thrombocytopenia (if the clinic uses heparin to maintain intravenous cannula patency).

• Subject has used medications known to affect the elimination of serum creatinine (example (e.g); trimethoprim or cimetidine) or competitors of renal tubular secretion (e.g., probenecid) within 30 days before dosing.

• Subject must abstain from taking prescription or nonprescription drugs (including vitamins and dietary or herbal supplements), unless specified, within 7 days (or 14 days if the drug is a potential strong enzyme inducer) or 5 half-lives (whichever is longer) prior to study drug administration until completion of the Follow-Up Visit, unless, in the opinion of the investigator and Sponsor, the medication will not interfere with the study. Any exceptions (including subjects with hepatic impairment that will be on medications during the study), will be discussed with the sponsor or medical monitor on a case-by-case basis and the reasons will be documented.

• Previous exposure to gepotidacin, within 12 months prior to study drug administration.

• Subject has participated in a clinical trial and has received an investigational product within the following time period prior to study drug administration 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 with normal hepatic function has presence of hepatitis B surface antigen or positive hepatitis C antibody test result at Screening or within 3 months prior to study drug administration. Subject with hepatic impairment has evidence of recent, acute infection with hepatitis B and/or hepatitis C within preceding 6 months. Hepatically impaired subjects with chronic hepatitis B or C (duration >6 months) will be eligible for enrolment.

• A positive test for human immunodeficiency virus antibody.

• Subject must be able to abstain from alcohol and limit use of nicotine and/or nicotine-containing products (up to 5 cigarettes/day is acceptable for subjects with hepatic impairment) for 24 hours before the start of dosing until after collection of the final PK sample. A positive alcohol or cotinine test is not exclusionary for subjects with hepatic impairment.

• Subject has clinically significant abnormal findings in serum chemistry, hematology, or urinalysis results obtained at Screening or Day -1, other than those associated with underlying hepatic conditions or other stable medical conditions consistent with the disease process in subjects with hepatic impairment.

• Subject with normal hepatic function has a baseline corrected QT interval using the Fridericia formula (QTcF) of >450 milliseconds (msec) and subject with hepatic impairment has a baseline QTcF of >480 msec.

• Donation of blood in excess of 500 milliliter (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.

• Subject is unable to comply with all study procedures, in the opinion of the investigator.

• Subject should not participate in the study, in the opinion of the investigator or Sponsor.

• Subjects with a pre-existing condition (except hepatic impairment) interfering with normal gastrointestinal (GI) anatomy or motility that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Subjects with a history of inflammatory bowel disease should be excluded. Subjects with a history of pepticulceration or pancreatitis within the preceding 6 months of screening, should be excluded.

• Subject with any previous GI surgery (except appendectomy or gall bladder removal >3 months prior to Screening) may be enrolled in this study only if, in the opinion of the investigator and the medical monitor, it is not expected to interfere with the study procedures or to pose an additional safety risk to the subject.

• Subject receiving lactulose who are medically unable to halt lactulose administration from 8 hours before dosing with study drug to 4 hours after dosing with study drug.

• Subjects with clinically active severe encephalopathy (grade 3 or 4) as judged by the investigator or significant central nervous system disease (e.g., dementia or seizures) which the investigator considers will interfere with the informed consent, conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject. Subjects with a prior history of severe encephalopathy, who are currently treated for this condition will receive the appropriate score for encephalopathy.

• Subjects with estimated creatinine clearance (Clcr) <=50 mL/minute (calculated by the Cockcroft-Gault Formula). If the result calculated by Cockcroft-Gault is between 40 and 50 mL/minute, then the site may complete a 24-hour urine collection to more specifically calculate the Clcr. A Clcr value <=50 mL/minute via 24-hour urine collection is also exclusionary.

• History of gastric or esophageal variceal bleeding within the past 6 months and for which varices have not been adequately treated with medication and/or surgical procedures.

• Subjects with electrolyte imbalance whose serum sodium levels are <=125 millimole per Liter (mmol/L); potassium levels are <=2.5 mmol/L; or calcium levels are <=6.1 mmol/L.

• Presence of hepatopulmonary or hepatorenal syndrome.

• Primary cholestatic liver diseases.

• History of liver transplantation or subjects in the severe hepatic impairment group that are expecting a liver transplant during the study participation period.

• Subjects with signs of active bacterial infection (including active spontaneous bacterial peritonitis).

• Subjects with transjugular intrahepatic portosystemic shunt placement within the past 3 months.

• Subjects with unstable cardiac function or subjects with hypertension whose blood pressure, that is not well controlled (based on the investigator's discretion).

• Diabetic subjects whose diabetes that is not controlled (based on the investigator's discretion).

Related Conditions & MeSH terms

• Bacterial Infections
• Infections, Bacterial

Intervention

Drug:
• Gepotidacin
It is an immediate-release tablet (1500 mg (2 x 750 mg), containing gepotidacin (free base) an inactive formulation excipients.

Locations

Country	Name	City	State
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Orlando	Florida

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	Biomedical Advanced Research and Development Authority

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Plasma Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinity (AUC[0-inf]) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate pharmacokinetic (PK) parameters. PK parameter population consist of all participants in the PK Population, for whom valid and evaluable PK parameters were derived. This population was used in the assessment and characterization of PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Primary	Maximum Observed Concentration (Cmax) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC [0-t]) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Time to First Occurrence (Tmax) of Cmax for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Apparent Oral Clearance (CL/F) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Apparent Volume of Distribution of the Terminal Phase (Vz/F) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Terminal-phase Rate Constant (Lambda_z) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Terminal Phase Half Life (t1/2) for Plasma Gepotidacin	Blood samples were collected from participants at indicated time points after the administration of study treatment to investigate PK parameters.	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose
Secondary	Number of Participants With Abnormal Electrocardiogram (ECG) Findings	Single 12-lead ECG was obtained in a semi-supine position after 5 minutes rest using an ECG machine. Safety Population consists of all participants who received at least 1 dose of study drug and had at least one postdose safety assessment. Number of participants with abnormal-clinically significant and abnormal-not clinically significant values has been presented. Absolute QTc Interval >450 milliseconds (msec), absolute PR interval <110 msec and absolute QRS interval <75 msec was considered as clinically significant ECG findings.	1.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours post-dose
Secondary	Change From Baseline Values in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Vital signs were measured in a semi-supine position after 5 minutes rest. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline (Day 1) and at 1.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours post-dose
Secondary	Change From Baseline Values in Heart Rate	Vital signs was measured in a semi-supine position after 5 minutes rest. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline (Day 1) and at 1.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, and 48 hours post dose
Secondary	Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect, associated with liver injury and impaired liver function or any other situations as per medical or scientific judgment.	Up to Day 15
Secondary	Number of Participants With Toxicity Grading 3 or Higher for Clinical Chemistry Parameters	Blood samples were collected to measure the number of participants with toxicity grades higher than 3 or 4, for urea, Creatine kinase (CK), creatinine, glucose, sodium, potassium, calcium, Aspartate Aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) levels, total and direct bilirubin, total protein, and albumin.	Up to Day 15
Secondary	Change From Baseline Values for Clinical Chemistry Parameters: ALT, ALP, AST and CK	Blood samples were collected to analyze clinical chemistry parameters including: ALT, ALP, AST and CK. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline and at Day 2
Secondary	Change From Baseline Values for Clinical Chemistry Parameters: Albumin and Protein	Blood samples were collected to analyze clinical chemistry parameters including albumin and protein. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline and at Day 2
Secondary	Change From Baseline Values for Clinical Chemistry Parameters: Bilirubin, Direct Bilirubin and Creatinine	Blood samples were collected to analyze clinical chemistry parameters including bilirubin, direct bilirubin and creatinine. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline and at Day 2
Secondary	Change From Baseline Values for Clinical Chemistry Parameters: Calcium, Glucose, Potassium, Sodium and Urea	Blood samples were collected to analyze clinical chemistry parameters including calcium, glucose, potassium, sodium and urea. Baseline is defined as Day 1 (Pre-Dose). Change from Baseline is calculated as the value at the post-dose visit minus the Baseline value.	Baseline and at Day 2
Secondary	Number of Participants With Toxicity Grading 3 or Higher for Hematology Parameters	Blood samples were collected to measure the number of participants with toxicity grades higher than 3 or 4 for blood neurtophils and blood platelets.	Up to 15 days
Secondary	Number of Participants With Toxicity Grading 3 or Higher for Urinalysis Parameters	Urine samples were collected and specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones were analyzed by dipstick method.	Up to 15 days
Secondary	Number of Participants With Abnormal Findings During Physical Examinations	A complete physical examination included, at a minimum, assessments of the skin, cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight were also measured and recorded. A brief physical examination included, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.	Pre-dose up to 31 days prior to dosing
Secondary	Total Unchanged Drug (Ae_total) and Amount of Drug Excreted in Urine in a Time Intervals (Ae (t1-t2) for Gepotidacin	Urine samples were collected from participants at indicated time points. Ae_total was calculated by adding all the fractions of drug collected over all the allotted time intervals. Ae (t1-t2) was the amount of drug excreted in urine in time intervals for predose, 0 to 6, 6 to 12, 12 to 24, 24 to 36, and 36 to 48 hours after dosing for participants with hepatic impairment; and predose, 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 for participants with normal hepatic function. It was calculated by multiplication of the urine concentration for a time interval and the length of this time interval.	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
Secondary	Percentage of the Given Dose of Drug Excreted in Urine (Fe%)	Urine samples were collected from participants at indicated time points. Percentage of the given dose of drug excreted in urine was calculated as: (Ae_total divided by Dose) and multiplied by 100.	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
Secondary	Renal Clearance (CLr) of Gepotidacin	Urine samples were collected from participants at indicated time points. Renal clearance for gepotidacin was calculated as Ae_total divided by AUC (0-t).	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
Secondary	AUC(0-12) of Gepotidacin	Urine samples were collected from participants at indicated time points to evaluate AUC(0-12) PK parameter of gepotidacin.	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours and 8-12 hours post dose
Secondary	AUC(0-24) of Gepotidacin	Urine samples were collected from participants at indicated time points to evaluate AUC(0-24) PK parameter of gepotidacin.	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours and 12-24 hours post dose
Secondary	AUC(0-48) of Gepotidacin	Urine samples were collected from participants at indicated time points to evaluate AUC(0-48) PK parameter of gepotidacin.	Pre-dose, 0-2 hours, 2-4 hours, 4-6 hours, 6-8 hours, 8-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post dose