Phase 1
Completed N=16
A Study to Compare the Pharmacokinetics (PK) of GSK2982772 Following Administration of Different Modified Release (MR) Formulations in Capsule and MR Tablet Formulations Relative to an Immediate Release (IR) Tablet Formulation and to Check the PK of MR Formulation in Capsule Following Repeat Doses
Source: ClinicalTrials.gov NCT03266172 ↗Enrolled (actual)
16
Serious AEs
0.6%
Results posted
Jan 2020
Primary outcomePrimary: Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 in IR Formulation: Part A — 6.305 Hours*microgram per milliliter
Summary
GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1) kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions. PK data from the first time in human (FTIH) study for GSK2982772 showed that the half life of GSK2982772 was short (approximately 2 to 3 hours). A once daily (QD) formulation would be more convenient from a subject perspective and could offer the advantage of providing a flatter GSK2982772 concentration time profile. Following completion of Parts A and B, it was determined that the slowest minitab formulation provided a PK profile suitable for QD dosing but this formulation was susceptible to a food effect. This study will evaluate the pharmacokinetics of GSK2982772 following administration of different minitab MR formulations in a capsule relative to an IR reference tablet formulation, the pharmacokinetics of selected MR formulation in capsule following repeat doses for 3 days and to compare the pharmacokinetics of GSK2982772 following administration of MR tablet formulations in the fed and fasted state relative to an IR tablet formulation. The study is divided into three parts: Part A will be a non-randomized 6 periods, sequential, 6-way fixed sequence design in which up to 4 MR minitab formulations in a capsule will be evaluated. Periods 1, 2, and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration (nominally 10 hours), and IR tablet respectively. Periods 4, 5 and 6 will have flexible dose regimen and it will depend on the outcomes of Period 1 to 3. Subjects will be admitted to the clinic the previous day before dosing. Each in-patient period will consist of 3 days and 2 nights followed by a minimum washout period of 7 days between doses, for both Part A and C. In Part A and C, 16 healthy subjects will be enrolled such that at least 12 evaluable subjects complete the study. Part B will be an open-label, repeat dose study in which the selected MR minitab formulation in capsule will be evaluated. Each in-patient period will consist of 5 days and 4 nights. There will be a minimum of 7 days washout period between the last morning dose of one period and the first dose of the next period. In Part B, 10 healthy subjects will be enrolled such that at least 6 evaluable subjects complete the study. Part C of the study will be a non-randomised 6 period, sequential, fixed sequence crossover design in which MR tablet formulations will be evaluated. Periods 1 and 2 will evaluate single dose administration of a 240 milligram (mg) MR tablet and the 240 mg IR tablet (reference), respectively. Periods 3, 4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of Periods 1 and 2.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 in IR Formulation: Part A |
6.305 | — |
| PRIMARY AUC(0-inf) of GSK2982772 in MT Formulation :Part A |
3.852; 4.482; 5.314 | — |
| PRIMARY Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of GSK2982772 in IR Formulation : Part A |
6.258 | — |
| PRIMARY AUC(0-t) of GSK2982772 in MT Formulation: Part A |
3.805; 4.449; 4.720 | — |
| PRIMARY Area Under the Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK2982772 in IR Formulation: Part A |
6.256 | — |
| PRIMARY AUC(0-24) of GSK2982772 in MT Formulation: Part A |
3.558; 4.255; 4.580 | — |
| PRIMARY Area Under the Curve From Time Zero to 12 Hours (AUC[0-12]) of GSK2982772 in IR Formulation: Part A |
5.967 | — |
| PRIMARY AUC(0-12) of GSK2982772 in MT Formulation: Part A |
2.106; 3.066; 3.573 | — |
| PRIMARY Maximum Observed Concentration (Cmax) of GSK2982772 in IR Formulation: Part A |
1.375 | — |
| PRIMARY Cmax of GSK2982772 in MT Formulation: Part A |
0.277; 0.439; 0.624 | — |
| PRIMARY Concentration at 12 Hours Post-dose (C12hour) of GSK2982772 in Part A |
0.220; 0.209; 0.208; 0.045 | — |
| PRIMARY Concentration at 24 Hours Post-dose (C24hour) of GSK2982772 in Part A |
0.058; 0.046; 0.030; 0.006 | — |
| PRIMARY Relative Bioavailability (Frelformulation) Based on AUC (0-inf) of GSK2982772 in Part A |
72.77; 60.53 | — |
| PRIMARY Frelformulation Based on AUC (0-24) of GSK2982772 in Part A |
68.18; 57.54 | — |
| PRIMARY Frelformulation Based on Cmax of GSK2982772 in Part A |
32.13; 20.39 | — |
| PRIMARY Ratio of Cmax to C12hour of GSK2982772 in IR Formulation: Part A |
36.485 | — |
| PRIMARY Ratio of Cmax to C12hour of GSK2982772 in MT Formulation: Part A |
1.284; 2.265; 3.240 | — |
| PRIMARY Ratio of Cmax to C24hour of GSK2982772 in IR Formulation: Part A |
312.851 | — |
| PRIMARY Ratio of Cmax to C24hour of GSK2982772 in MT Formulation: Part A |
6.119; 10.790; 22.915 | — |
| PRIMARY Time to Cmax (Tmax) of GSK2982772 in IR Formulation: Part A |
2.000 | — |
| PRIMARY Tmax of GSK2982772 in MT Formulation: Part A |
10.000; 4.000; 6.000 | — |
| PRIMARY AUC(0-inf) of GSK2982772 for IR Formulation in Part C: Fasted State |
14.797 | — |
| PRIMARY AUC(0-inf) of GSK2982772 for MM Formulation in Part C: Fasted State |
13.417; 22.493 | — |
| PRIMARY AUC(0-t) of GSK2982772 for IR Formulation in Part C: Fasted State |
14.621 | — |
| PRIMARY AUC(0-t) of GSK2982772 for MM Formulation in Part C: Fasted State |
9.676; 20.009 | — |
| PRIMARY AUC(0-24) of GSK2982772 for IR Formulation in Part C: Fasted State |
14.619 | — |
| PRIMARY AUC(0-24) of GSK2982772 for MM Formulation in Part C: Fasted State |
8.769; 18.177 | — |
| PRIMARY AUC (0-12) of GSK2982772 for IR Formulation in Part C: Fasted State |
13.500 | — |
| PRIMARY AUC (0-12) of GSK2982772 for MM Formulation in Part C: Fasted State |
6.096; 12.508 | — |
| PRIMARY Cmax of GSK2982772 for IR Formulation in Part C: Fasted State |
2.938 | — |
| PRIMARY Cmax of GSK2982772 for MM Formulation in Part C: Fasted State |
0.918; 2.010 | — |
| PRIMARY C12 of GSK2982772 in Part C: Fasted State |
0.197; 0.346; 0.671 | — |
| PRIMARY C24 of GSK2982772 in Part C: Fasted State |
0.025; 0.162; 0.351 | — |
| PRIMARY Ratio of Cmax to C12hour of GSK2982772 for IR Formulation in Part C: Fasted State |
17.158 | — |
| PRIMARY Ratio of Cmax to C12hour of GSK2982772 for MM Formulation in Part C: Fasted State |
2.892; 3.551 | — |
| PRIMARY Ratio of Cmax to C24hour of GSK2982772 for IR Formulation in Part C: Fasted State |
138.239 | — |
| PRIMARY Ratio of Cmax to C24hour of GSK2982772 for MM Formulation in Part C: Fasted State |
6.026; 7.991 | — |
| PRIMARY Frelformulation Based on AUC (0-t) of GSK2982772 in Part C: Fasted State |
66.18 | — |
| PRIMARY Frelformulation Based on AUC (0-24) of GSK2982772 in Part C: Fasted State |
59.98 | — |
| SECONDARY Frelformulation Based on AUC (0-inf) of GSK2982772 After a High Fat Meal in Part A |
123.64 | — |
| SECONDARY Frelformulation Based on Cmax of GSK2982772 After a High Fat Meal in Part A |
225.07 | — |
| SECONDARY AUC(0-24) of GSK2982772 in Part B |
4.669; 8.807; 9.662; 5.010; 9.867; 10.948 | — |
| SECONDARY Cmax of GSK2982772 in Part B |
0.417; 0.707; 0.888; 0.398; 0.794; 1.080 | — |
| SECONDARY Tmax of GSK2982772 in Part B |
4.058; 4.067; 4.000; 4.000; 5.025; 4.000 | — |
| SECONDARY AUC (0-24) of GSK2982772 After Meal in Part C |
17.505; 8.734; 21.543 | — |
| SECONDARY Cmax of GSK2982772 After Meal in Part C |
1.547; 1.064; 3.151 | — |
| SECONDARY C12 of GSK2982772 After Meal in Part C |
0.706; 0.739; 0.317 | — |
| SECONDARY AUC(0-t) of GSK2982772 After Meal in Part C |
19.147; 9.202; 22.712 | — |
| SECONDARY AUC(0-inf) of GSK2982772 After Meal in Part C |
18.941; 9.995; 24.367 | — |
| SECONDARY AUC(0-12) of GSK2982772 After Meal in Part C |
17.111; 10.241; 6.771 | — |
| SECONDARY Frelformulation Based on AUC (0-t) of GSK2982772 After Meal in Part C |
94.69; 113.51; 91.13 | — |
| SECONDARY Frelformulation Based on Cmax of GSK2982772 After Meal in Part C |
76.56; 156.77; 113.81 | — |
| SECONDARY Tmax of GSK2982772 After Meal in Part C |
4.000; 4.000; 5.017 | — |
| SECONDARY Number of Participants With Adverse Events (AE) and Serious AEs (SAE) in Part A |
4; 5; 1; 2; 0; 1 | — |
| SECONDARY Number of Participants With AE and SAE in Part B |
1; 3; 1; 0; 0; 0 | — |
| SECONDARY Number of Participants With AE and SAE in Part C |
3; 3; 3; 4; 2; 1 | — |
| SECONDARY Number of Participants With Emergent Clinical Chemistry Results by Potential Clinical Importance Criteria: Part A |
0; 0; 0; 0; 16; 13 | — |
| SECONDARY Number of Participants With Emergent Hematology Results by Potential Clinical Importance Criteria: Part A |
0; 0; 0; 0; 16; 13 | — |
| SECONDARY Number of Participants Abnormal Urinalysis Dipstick Results: Part A |
0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Emergent Clinical Chemistry Results by Potential Clinical Importance Criteria: Part B |
0; 0; 0; 10; 10; 6 | — |
| SECONDARY Number of Participants With Emergent Hematology Results by Potential Clinical Importance Criteria: Part B |
0; 0; 0; 10; 10; 6 | — |
| SECONDARY Number of Participants Abnormal Urinalysis Dipstick Results: Part B |
0; 0; 0 | — |
| SECONDARY Number of Participants With Emergent Clinical Chemistry Results by Potential Clinical Importance Criteria: Part C |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Emergent Hematology Results by Potential Clinical Importance Criteria: Part C |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants Abnormal Urinalysis Dipstick Results: Part C |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants Abnormal Electrocardiogram (ECG) Findings: Part A |
6; 8; 9; 9; 1; 0 | — |
| SECONDARY Number of Participants Abnormal ECG Findings: Part B |
4; 4; 2; 0; 0; 0 | — |
| SECONDARY Number of Participants Abnormal ECG Findings: Part C |
1; 4; 7; 5; 6; 3 | — |
| SECONDARY Change From Baseline in Blood Pressure: Part A |
-1.4; 4.3; -0.2; -6.2; -1.6; -2.5 | — |
| SECONDARY Change From Baseline in Heart Rate: Part A |
-4.4; -0.3; -2.5; 3.9; 4.8; 5.2 | — |
| SECONDARY Change From Baseline in Respiration Rate: Part A |
-0.4; 0.8; 0.0; -1.5; -0.6; -0.1 | — |
| SECONDARY Change From Baseline in Body Temperature: Part A |
0.02; 0.18; 0.05; 0.14; 0.07; -0.04 | — |
| SECONDARY Change From Baseline in Blood Pressure: Part B |
-0.5; 5.4; 1.2; 2.7; 1.5; 1.0 | — |
| SECONDARY Change From Baseline in Heart Rate: Part B |
0.0; -2.4; 7.3; 10.0; 8.8; 10.5 | — |
| SECONDARY Change From Baseline in Respiration Rate: Part B |
0.5; -2.0; -1.2; -0.1; -2.5; -1.5 | — |
| SECONDARY Change From Baseline in Body Temperature: Part B |
0.03; -0.01; 0.00; 0.06; 0.08; 0.07 | — |
| SECONDARY Change From Baseline in Blood Pressure: Part C |
-3.3; -0.6; -0.6; -4.9; 1.1; -0.2 | — |
| SECONDARY Change From Baseline in Heart Rate: Part C |
2.1; -5.3; 0.0; 7.3; 8.2; 8.2 | — |
| SECONDARY Change From Baseline in Respiration Rate: Part C |
1.7; 0.6; 0.9; -1.1; 1.8; 0.1 | — |
| SECONDARY Change From Baseline in Body Temperature: Part C |
-0.10; -0.05; -0.07; 0.23; 0.01; 0.10 | — |
Eligibility Criteria
Inclusion Criteria
- Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
- Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- Body weight greater than and equal to 50 kilogram (kg) and body mass index within the range 19.0 to 32.0 kilogram per meter square (kg/m^2) (inclusive).
- A male subject must agree to use a highly effective contraception during the treatment period and for at least 90 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 pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive during the treatment period and for at least 30 days before and 30 days after the last dose of study treatment.
- Capable of giving signed informed consent.
Exclusion Criteria
- History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
- Parts A and C only: Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a subject's lifetime.
- Part B only: Subjects with current history of suicidal ideation behavior as measured using the columbia-suicide severity rating scale (C-SSRS) or a history of attempted suicide.
- History of clinically significant psychiatric disorders as judged by the investigator. Depression requiring treatment in the last 2 years.
- History of herpes zoster (shingles) reactivation.
- History or diagnosis of obstructive sleep apnea.
- History of a significant respiratory disorder. Childhood asthma that has fully resolved is permitted.
- History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
- A positive diagnostic tuberculosis (TB) test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative.
- History of GI surgery (with exception of appendectomy).
- History of cholecystectomy or gall stones.
- Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
- ALT greater than 1.5 times upper limit of normal (ULN).
- Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percentage of total).
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
- Corrected QT interval (QTc) greater than 450 millisecond (msec).
- Past or intended use of over-the-counter or prescription medication including herbal medications within 7 days prior to dosing (paracetamol/acetaminophen [up to 2 gram (g) per day], hormone replacement therapy and hormonal contraception are permitted).
- Live or attenuated vaccine(s) within 30 days of enrolment, or plans to receive such vaccines during the study or plans to receive a vaccine within 30 days + 5 half-lives of the last dose of study medication.
- Subject in the study would result in loss of blood or blood products in excess of 500 milliliter (mL) within a 56 day period; therefore donation or loss of greater than 400 mL of blood within the previous 3 months.
- Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
- Current enrolment or past participation within the last 3
Data sourced from ClinicalTrials.gov (NCT03266172). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.