Rilapladib is a potent and selective inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), which was previously under development for the treatment of atherosclerosis and is currently being developed for the treatment of Alzheimer's disease. This study is a single-center, open-label, two-part study. The two study parts will run independently. Subjects dosed in one part of this study will not be permitted to participate in the other part. Part A will investigate the pharmacokinetic profile of rilapladib and its metabolites, SB-664601 and GSK1174379, after single dose and steady state dosing of rilapladib 250 milligram (mg) along with the biliary and urinary elimination pathways of rilapladib 250 mg. Part B will determine the effect of repeat administration of itraconazole on the PK of a single oral dose of rilapladib 25 mg. Healthy male and female subjects, aged 18-65 years, will be recruited for this study. Ten subjects will be recruited for Part A and 20 subjects will be recruited for Part B.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
White, round, biconvex, film coated tablet of 25 mg. Taken orally along with food.
White, round, biconvex, film coated tablet of 250 mg. Taken orally along with food.
100 mg capsule with a blue opaque cap and pink transparent body. Taken orally along with food.
Maximum observed concentration (Cmax), time of occurrence of Cmax (Tmax), area under the concentration-time curve over the dosing interval (AUC(0-Tau)) of rilapladib parent compound after single and repeat dosing, in part A of the study.
Cmax, Tmax and AUC (0-Tau) will be used to evaluate the pharmacokinetics of rilapladib after single and repeat dosing of rilapladib 250 mg.
Time frame: Day (D)1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hours (hrs) post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity)), and terminal phase half-life (T1/2) of rilapladib after repeat dosing, in part A of the study
AUC(0-infinity) and T1/2 of rilapladib will be used to evaluate the pharmacokinetics of rilapladib and its metabolites after repeat dosing of rilapladib 250 mg.
Time frame: D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13
Cmax, Tmax, AUC(0-tau), and area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration (AUC(0-t)) of SB-664601 and GSK1174379 after single and repeat dosing, in part A of the study
Cmax, Tmax, AUC(0-tau), and AUC(0-t) will be used to evaluate the pharmacokinetics of SB-664601 and GSK1174379 after single and repeat dosing of rilapladib 250 mg.
Time frame: D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13
AUC(0-infinity) and T1/2 of SB-664601 and GSK1174379 after repeat dosing, as data permit, in part A of the study.
AUC(0-infinity) and T1/2 will be used to evaluate the pharmacokinetics of SB-664601 and GSK1174379 after repeat dosing of rilapladib 250 mg.
Time frame: D1: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24 hrs post-dose, and D14: pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D16), 96 (D18), 144 (D20), 240 (D24) and 336 (D28) hrs post-dose. Pre-dose on Days 11, 12 and 13
AUC(0 infinity), AUC(0 t), and Cmax of rilapladib alone and in the presence of itraconazole in part B of the study.
AUC(0 infinity), AUC(0 t), and Cmax will be used to evaluate the effect of repeat oral dosing of itraconazole on the pharmacokinetics of single dose rilapladib 25 mg.
Time frame: D1 : Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D3), 96 (D5), 144 (D7) hours post dose, and on D 11: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D13), 96 (D15), 144 (D17) hours post dose
Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by adverse events (AEs), in part A of the study.
AEs will be collected from the start of Study Treatment and until the follow-up
Time frame: Up to Day 38
Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by 12-lead electrocardiogram (ECG) parameters, in part A of the study.
Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures pulse rate (PR), QRS, QT, and QTcF intervals.
Time frame: Up to Day 38
Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by measuring vital signs, in part A of the study.
Vital sign measurements will be performed in semi-supine or supine position after 10 minutes rest and will include systolic and diastolic blood pressure and pulse rate.
Time frame: Up to Day 38
Safety and tolerability of repeat oral doses of rilapladib 250 mg assessed by laboratory tests, in part A of the study.
Laboratory tests will include haematology, clinical chemistry, urinalysis and additional parameters.
Time frame: Up to Day 38
Tmax and T1/2 of rilapladib alone and in the presence of itraconazole, in part B of the study.
Tmax and T1/2 will be used to evaluate the effect of repeat oral dosing of itraconazole on the secondary PK parameters of rilapladib 25 mg.
Time frame: D1 : Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D3), 96 (D5), 144 (D7) hours post dose, and on D 11: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D13), 96 (D15), 144 (D17) hours post dose
AUC(0-infinity), AUC(0-t), Cmax, Tmax and T1/2 of rilapladib metabolites, SB-664601 and GSK1174379, alone and in the presence of itraconazole, in part B of the study.
AUC(0-infinity), AUC(0-t), Cmax, Tmax and T1/2 will be used to evaluate the effect of repeat oral dosing of itraconazole on the PK of the rilapladib metabolites, SB-554601 and GSK1174379, after single dose of rilapladib 25 mg.
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Time frame: D1 : Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D3), 96 (D5), 144 (D7) hours post dose, and on D 11: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 32, 48 (D13), 96 (D15), 144 (D17) hours post dose
Safety and tolerability of single oral dose of rilapladib 25 mg when dosed alone and concomitantly with itraconazole, assessed by AEs, in part B of the study.
AEs will be collected from the start of Study Treatment and until the follow-up
Time frame: Up to Day 27
Safety and tolerability of single oral dose of rilapladib 25 mg when dosed alone and concomitantly with itraconazole, assessed using ECG parameters, in part B of the study.
Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals.
Time frame: Up to Day 27
Safety and tolerability of single oral dose of rilapladib 25 mg when dosed alone and concomitantly with itraconazole, assessed as vital signs, in part B of the study.
Vital sign measurements will be performed in semi-supine or supine position after 10 minutes rest and will include systolic and diastolic blood pressure and pulse rate.
Time frame: Up to Day 27
Safety and tolerability of single oral dose of rilapladib 25 mg when dosed alone and concomitantly with itraconazole, assessed by laboratory tests, in part B of the study.
Laboratory tests will include haematology, clinical chemistry, urinalysis and additional parameters.
Time frame: Up to Day 27