This study will determine the effect of single and repeat administration of darapladib, a novel, selective, orally active inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2) currently under clinical development on the pharmacokinetics of a single oral dose of midazolam, a cytochrome P450 3A4 (CYP3A4) probe substrate. This study will investigate the inductive and inhibitory effect of darapladib on CYP3A4 metabolic pathway.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
26
The subjects will receive darapladib 160 mg once daily on Days 3-14. It is provided as Enteric coated, free base (micronized) 160 mg tablet.
The subjects will receive a single oral dose of midazolam 5 mg on Day 1, 3 and14. It is provided as syrup. Each mL of syrup contains midazolam hydrochloride equivalent to 2 mg midazolam
GSK Investigational Site
Baltimore, Maryland, United States
Maximum concentration (Cmax), and area under the time-concentration curve (AUC[0-inf]) of midazolam at Day 1and 14
The effects of repeat oral dosing of darapladib (160mg enteric coated \[EC\] tablet once daily \[QD\]) on the pharmacokinetic parameters - Cmax and AUC(0-infinity\[inf\]) of a single oral dose of midazolam (5 mg) will be evaluated
Time frame: Day 1 and 14
AUC(0-inf), Cmax, time to maximum concentration (tmax) and terminal half-life (t1/2) of midazolam at Days 3 and 14
The effects of single oral dose of darapladib (160mg EC tablet QD) as compared to multiple oral doses of darapladib on the pharmacokinetic parameters - Cmax, AUC(0-inf), tmax and t1/2 of the single oral dose of midazolam (5mg) will be evaluated
Time frame: Day 3 and 14
tmax and t1/2 of midazolam at Days 1 and 14
The effects of repeat oral dosing of darapladib (160mg EC tablet QD) on the other pharmacokinetic parameters- tmax and t1/2 of a single oral dose of midazolam (5mg) will be evaluated
Time frame: Day 1 and 14
AUC(0-inf), Cmax, tmax and t1/2 of midazolam at Days 1 and 3
The effects of single oral dose of darapladib (160mg EC tablet QD) on the other pharmacokinetic parameters- AUC(0-inf), Cmax, tmax and t1/2 of a single oral dose of midazolam (5mg QD) will be evaluated
Time frame: Day 1 and 3
Safety and tolerability of repeated oral doses of darapladib (160mg) in combination with midazolam (5mg) as assessed by frequency and severity of adverse events (AE), 12-Lead ECG, vital signs, oxygen saturation/pulse oximetry and safety laboratory tests
An AE is any untoward medical occurrence temporally associated with the use of the medicinal product, whether or not considered associated with the product. A serious AE is any medical occurrence that results in death, is life-threatening, require hospitalization or prolongation of an existing hospital stay, results in disability or incapacity, congenital anomaly, or is an "Hy's Law event (type of drug-induced liver injury)
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Time frame: Up to 56 days