An Open Label, Randomized, Single Dose, Crossover Study to Determine the Pharmacokinetics of Three Tablet Formulations of GSK2798745 in Healthy Subjects
Overview
- Phase
- Phase 1
- Intervention
- GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
- Conditions
- Heart Failure, Congestive
- Sponsor
- GlaxoSmithKline
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Area under the curve (AUC) of GSK2798745
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
GSK2798745 is being developed as a novel therapeutic intervention for the treatment of pulmonary edema associated with heart failure (HF) and is currently under investigation in the form of a compounded capsule. This is an open-label, randomized, single-dose, crossover study with the purpose to determine the pharmacokinetics (PK) of three 2.4 milligrams (mg) tablet formulations of GSK2798745 in 12 healthy subjects. The three formulations developed for this study will be micronized GSK2798745 active pharmaceutical ingredient (API) (Tablet A), micronized GSK2798745 API with sodium lauryl sulfate (SLS) and hypromellose (Tablet B), milled GSK2798745 API with SLS and hypermellose (Tablet C), and Tablet D, which will be either A/B/C based on interim PK analysis of data from the first three treatment periods.
Following a 30-day screening period, subjects will be randomized to one of the 6 treatment sequences: Treatment sequence 1: ABCD, 2=CABD, 3=ACBD, 4=BACD, 5=BCAD, 6=CBAD over three 4-day treatment periods. For treatment period 4, the best formulation based on the interim analysis data from the three treatment periods will be evaluated under fed conditions. Each treatment period will be separated by a minimum of 7 (+14)-day washout period. The total duration of participation in the study will be approximately 11 weeks including the follow-up visit.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Between 18 and 75 years of age inclusive, at the time of signing the informed consent
- •Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures
- •Body weight \>=50 kg and body mass index within the range 18 - 32 kilogram (kg)/meter (m)\^2 (inclusive)
- •Male or female of non-child bearing potential:
- •A male subject with a female partner of child bearing potential is eligible to participate if he agrees to use contraception as mentioned in the protocol during the treatment period and for at least 7 days after the last dose of study treatment and refrain from donating sperm during this period A female subject is eligible to participate if she is not a woman of childbearing potential (WOCBP) as defined in the protocol.
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol
Exclusion Criteria
- •History of acute coronary syndromes including unstable angina or myocardial infarction within 6 months of screening
- •History of stroke or seizure disorder within 5 years of Screening
- •Active ulcer disease or gastrointestinal bleeding at the time of screening
- •Alanine transaminase (ALT) and bilirubin \>1.5x Upper limit of normal (ULN) is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- •QT interval corrected according to Fridericia's formula (QTcF) \>450 milliseconds (msec)
- •History or current evidence of any serious or clinically significant gastrointestinal, renal, endocrine, neurologic, hematologic or other condition that is uncontrolled on permitted therapies or that would, in the opinion of the investigator or the Medical Monitor, make the subject unsuitable for inclusion in this study
- •Urinary cotinine levels indicative of current smoking or regular use of tobacco- or nicotine-containing products at time of screening (cotinine levels \>200 nanogram \[ng\]/millimeter \[mL\])
- •History of alcohol abuse within 6 months of the study based on the following criteria:
- •An average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 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
Arms & Interventions
GSK2798745 ABCD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 ABCD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 ABCD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
GSK2798745 CABD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 CABD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 CABD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
GSK2798745 ACBD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 ACBD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 ACBD treatment sequence
Subjects will be given 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
GSK2798745 BACD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 BACD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 BACD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
GSK2798745 BCAD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 BCAD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 BCAD treatment sequence
Subjects will be given 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
GSK2798745 CBAD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API without SLS and hypermellose (Tablet A)
GSK2798745 CBAD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 Micronized API with SLS and hypermellose (Tablet B)
GSK2798745 CBAD treatment sequence
Subjects will be given 2.4 mg GSK2798745 (milled API with SLS and hypromellose) in fasted state (treatment C), 2.4 mg of GSK2798745 (micronized API with SLS and hypromellose) in fasted state (treatment B), 2.4 mg single oral doses of GSK2798745 (micronized API without SLS and hypromellose) in fasted state (treatment A), and GSK2798745 tablet in fed state (treatment D) in either treatment periods 1, 2, or 3; the three treatment periods will each be separated by a minimum washout period of 7 days
Intervention: GSK2798745 milled API without SLS and hypermellose (Tablet C)
Outcomes
Primary Outcomes
Area under the curve (AUC) of GSK2798745
Time Frame: Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods
AUC will be determined following a single oral dose of GSK2798745 under fasted conditions (Treatment periods 1-3) and fed conditions (Treatment period 4)
Maximum plasma concentration (Cmax) of GSK2798745
Time Frame: Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods
Cmax will be determined following a single oral dose of GSK2798745 under fasted conditions (Treatment periods 1-3) and fed conditions (Treatment period 4)
Secondary Outcomes
- Safety and tolerability of single dose of GSK2798745 as assessed by weight assessments(Up to 11 weeks)
- Time to maximum observed concentration (Tmax) of GSK2798745(Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods)
- AUC of GSK2798745 following a standard Food Drug Administration (FDA) high fat, high calorie meal(Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in treatment period 4)
- Pulse rate as a measure of safety and tolerability of GSK2798745(Up to 11 weeks)
- Safety and tolerability of single dose of GSK2798745 as assessed by liver function tests (LFTs)(At Baseline (Day -1))
- Elimination half-life (T1/2) of GSK2798745(Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in each of the treatment periods)
- Cmax of GSK2798745 following a standard FDA high fat, high calorie meal(Blood samples will be collected at the following time points: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 15 (Day 1), 24 and 36 (Day 2), 48 (Day 3) and 72 hours (Day 4) post dose in treatment period 4)
- Systolic and diastolic blood pressure as a measure of safety and tolerability of GSK2798745(Up to 11 weeks)
- Respiratory rate as a measure of safety and tolerability of GSK2798745(Up to 11 weeks)
- Safety and tolerability of single dose of GSK2798745 as assessed by electorcardiograms (ECGs)(Up to 11 weeks)
- Safety and tolerability of single dose of GSK2798745 as assessed by hematology(At Baseline (Day -1))
- Safety and tolerability of single dose of GSK2798745 as assessed by clinical chemistry(At Baseline (Day -1))
- Safety and tolerability of single dose of GSK2798745 as assessed by urinalysis(At Baseline (Day -1))
- Safety and tolerability of single dose of GSK2798745 as assessed by appetite assessments(Up to 11 weeks)
- Safety and tolerability of single dose of GSK2798745 as assessed by troponin measurement(At Baseline (Day -1) and 24 hours post dose on Day 2)
- Number of subjects with any adverse events (AEs) as a measure of safety and tolerability of GSK2798745(Up to 11 weeks)