A Phase I, Open-Label, Parallel-Group, Two-Part Study to Evaluate the Pharmacokinetics and Safety of GSK2336805 in Subjects With Hepatic Impairment and Healthy Matched Control Subjects (HAI117380)
Overview
- Phase
- Phase 1
- Intervention
- GSK2336805
- Conditions
- Hepatitis C
- Sponsor
- GlaxoSmithKline
- Enrollment
- 31
- Locations
- 1
- Primary Endpoint
- Composite of plasma pharmacokinetic (PK) parameters of GSK2336805
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This is a single-dose, open-label, two part, parallel group study. This study is being conducted to determine the pharmacokinetics, safety and tolerability of GSK2336805 in subjects with varying degrees of hepatic impairment. Part 1 of the study will enroll subjects with mild and moderate hepatic impairment and healthy control subjects matched to the subjects in the moderate hepatic impairment category. The decision to commence Part 2 will be based on a review of the preliminary safety and pharmacokinetic data from subjects with moderate hepatic impairment. Part 2 will enroll subjects with severe hepatic impairment. Additionally, based on emergent data from Part 1, matched controls to the severe hepatic group may be enrolled (optional). Due to the potential difficulty in identifying eligible subjects with severe hepatic impairment, the study may be stopped prior to full enrollment in Part 2, provided that a minimum of 4 evaluable subjects with severe hepatic impairment have been enrolled. The study will consist of a Screening visit, a single dose Treatment Period and a Follow-up visit. Subjects will be screened for eligibility criteria within 30 days of enrolment. Subjects will be admitted to the clinical unit on Day -1; each subject will receive a single dose of GSK2336805 on Day 1 and will remain in the clinical unit for 5 days (check-out on Day 4). The follow-up visit will be conducted within 7-10 days after Day 1 dosing.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female subjects aged 18 to 74 years inclusive, at the time of signing the informed consent.
- •Body weight \>=45 kilogram (kg) for men and women and body mass index (BMI) within the range 17- 41 kg/meter square (m\^2) for hepatically impaired subjects; healthy matched control subjects will be matched to BMI +/- 20% and must also remain in the BMI range of 17- 41 kg/m\^
- •A female subject is eligible to participate if she is of non-childbearing potential (postmenopausal defined as 12 months of spontaneous amenorrhea or pre-menopausal females with a documented tubal ligation or hysterectomy).
- •Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the follow up visit.
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- •The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.
- •Ability and willingness to abstain from alcohol-containing beverages/foods from 48 hours prior to entry in the clinical study centre until discharge.
- •Supplemental inclusion criteria for Healthy Volunteer subjects only: A male or female is eligible for study participation if he/she is healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and electrocardiogram (ECG), including no cardiac, pulmonary, hepatic, biliary, gastrointestinal, or renal disorders (defined as serum creatinine \>1.5 milligram(mg)/decilitre (dL) or a calculated creatinine clearance (CrCl)\<50 millilitre (mL)/ minute(min), or cancer within the past 5 years (except localized or in situ cancer of the skin). 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 and the Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. A single repeat laboratory evaluation is allowed for eligibility determination. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin less than the upper limits of normal. The subject's systolic blood pressure is inside the range of 90-140 millimeter of mercury (mmHg) and diastolic blood pressure is inside the range of 45-90 mmHg and heart rate is inside the range of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male subjects.
- •Supplemental inclusion criteria for all hepatically impaired subjects: 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.
- •Subjects whose platelets are greater than or equal to 30,000 x 10\^9/Liter of blood who have not had any major bleeding episodes within the past 6 months.
Exclusion Criteria
- •Pregnant females as determined by positive serum or urine Human Chorionic Gonadotropin (hCG) test at screening or prior to dosing.
- •Lactating females.
- •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 (g) 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.
- •A positive test for human immunodeficiency virus (HIV) antibody.
- •Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
- •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).
- •Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pummelos, satsuma, ugli, tangerine, and tangelo, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
- •Use of prescription or non-prescription drugs, vitamins, and herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication. Hepatically impaired subjects requiring prescription or non-prescription drugs may be acceptable provided the medications are not on the Prohibited Medications List of the protocol and in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.
- •History or presence of allergy or intolerance to the study drugs or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. In addition, if heparin is used during pharmacokinetic (PK) sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
- •The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. For hepatically impaired subjects, a positive drug screen will be allowed if it is due to a prescribed medication, provided that medication is not on the Prohibited Medications List of the protocol.
Arms & Interventions
Part 1 Cohort 1 - Mild hepatic impairment
Subjects with mild hepatic impairment will be enrolled in Cohort 1 and will receive a single dose of 60 mg GSK2336805
Intervention: GSK2336805
Part 1 Cohort 2 - Moderate hepatic impairment
Subjects with moderate hepatic impairment will be enrolled in Cohort 2 and will receive a single dose of 60 mg GSK2336805
Intervention: GSK2336805
Part 1 Cohort 3 - Matched healthy volunteers to Cohort 2
Control subjects will be matched for gender, age (+/- 10 years), body mass index (BMI) (+/- 20%), and smoking status to the subjects in the moderate hepatic impairment arm. These healthy volunteers will receive a single dose of 60 mg GSK2336805
Intervention: GSK2336805
Part 2 Cohort 4 - Severe hepatic impairment
Subjects with severe hepatic impairment will be enrolled in Cohort 2 and will receive a single dose of 60 mg GSK2336805. The decision to move forward into Part 2 (severe hepatic impairment) will be based on a review of the preliminary safety and pharmacokinetic data from subjects with moderate hepatic impairment
Intervention: GSK2336805
Part 2 Cohort 5 - Matched healthy volunteers to Cohort 4
Based on emerging data from Part 1, the sponsor may decide to enroll matched controls to the severe hepatic group (i.e. in case of a change in dose or the demographics of the severe hepatic group are not well matched with the moderate control data). The subjects in this optional control cohort will be matched for gender, age (+/- 10 years), BMI (+/- 20%), and smoking status to the subjects in the severe hepatic impairment category
Intervention: GSK2336805
Outcomes
Primary Outcomes
Composite of plasma pharmacokinetic (PK) parameters of GSK2336805
Time Frame: Day 1: 0.25 hours (h) predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 (Day 2), 36, 48(Day 3), 60 and 72(Day 4) h post-dose
The following pharmacokinetic parameters will be determined: area under the plasma concentration time curve (AUC)- from time zero to infinity \[AUC(0-inf)\], from time zero to the last quantifiable time points \[AUC(0-t)\], and from time zero to 24 hours \[AUC(0-24)\]; maximum observed plasma concentration (Cmax); time to Cmax (tmax); concentration at 24hour post-dose (C24); absorption lag time (tlag); apparent oral clearance (CL/F), apparent volume of distribution after oral administration (Vz/F), and half-life (t½). These will be compared in subjects with hepatic impairment to healthy volunteers
Secondary Outcomes
- Unbound concentration and unbound fraction of GSK2336805 in plasma(Day 1: 2, 12 and 24 h post dose)
- Safety and tolerability of GSK2336805 as assessed by adverse events (AEs), concurrent medications, clinical laboratory, electrocardiograms (ECGs) and vital sign parameters(Up to 10 days)
- Composite of plasma PK parameters of GSK2336805 in subjects with hepatic impairment compared with PK parameters of non-cirrhotic subjects with chronic Hepatitis C (CHC)(Day 1: 0.25 hours (h) predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 (Day 2), 36, 48 (Day 3), 60 and 72 (Day 4) h post-dose)