Darapladib (SB-480848) is a novel, selective, orally active inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2) currently under clinical development by GlaxoSmithKline as a potential anti-atherosclerosis agent for reduction of major adverse cardiovascular (CV) events in patient populations with chronic coronary heart disease and after an acute coronary syndrome. This study will determine the effect of repeated administration of diltiazem on the pharmacokinetics of a repeated administration of darapladib. A drug interaction study with a moderate CYP3A4 inhibitor is warranted to provide guidance to prescribing physicians.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Enteric coated, free base (micronized) white round tablet, 160mg, Oral/repeat dose/10 days (Treatment Period 1), 14 days (Treatment Period 2)
Extended release, Blue capsule imprinted with cardizem CD and 240mg on one end, 240 mg, Oral/repeat dose/17 days
GSK Investigational Site
Baltimore, Maryland, United States
AUC(0-24h) of darapladib
The area under the concentrations-time curve (AUC0-24) from the time of administration of darapladib up to 24 h after administration.
Time frame: Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)
Cmax of darapladib
The maximum concentration (Cmax) was obtained directly from the measured concentration-time curves.
Time frame: Up to 32 days. (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose)
Number of subjects with adverse event (AE).
AE's will be collected from the start of study treatment to the last follow up.
Time frame: Up to 70 days.
12-Lead electrocardiogram (ECG) assessment as a measure of safety and tolerability
Single 12-lead ECGs will be obtained after the subject has been in a supine position for at least 10 minutes at each timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.
Time frame: Up to 42 days. (Screening Day 32 and Follow up [Day 38 to 42]).
Vital signs assessment as a measure of safety and tolerability
Systolic and diastolic blood pressure and pulse rate measurements will be recorded after the subject has been resting in a semi-supine or supine position for at least 10 minutes.
Time frame: Up to 42 days (Screening, Day -1, 15, 16, 22, 28, 32 and Follow up [Day 38 to 42]).
Safety laboratory tests assessment as a measure of safety and tolerability
Hematology, clinical chemistry, urinalysis were assessed.
Time frame: Up to 42 days (Screening, Day -1, 15, 32 and Follow up [Day 38 to 42]).
Tmax and t1/2 of darapladib.
Tmax is defined as the time required reaching the maximum concentration of the drug in the plasma after its administration. t1/2 is defined as the time taken to reach half the concentration of the drug after administration.
Time frame: Up to 32 days (PK samples will be collected on Days 8, 9, 26 and 27 at predose. Day 10 and Day 28 predose and at 0.5, 1, 2, 3, 4, 6, 9, 12, 18, 24, 32, 48, 72, and 96 hours post-dose.
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