Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of GSK2647544 in healthy volunteers

Abstract

Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…GSK2647544 has been evaluated as for the safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers in phase 1 clinical trials [123]. The compound was generally well tolerated and had a reasonable PK-PD profile [124]. In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor [ 18 F]GSK2647544 was manufactured for use in a PET biodistribution phase Ι study [125].…”

Lipoprotein‐associated phospholipase A2: The story continues

“…In the past few years, our group reported two series of novel Lp‐PLA2 inhibitors based on the pyrimidone scaffold, with a favorable selective inhibition toward Lp‐PLA2. Previous studies revealed that GSK2647544 had an improved PK profile compared with darapladib in human subjects . Indeed, we detected greater plasma exposure of GSK2647544 than that of darapladib when dosed orally to SD rats (GSK2647544: C max , 0.78 μg/mL; AUC (0‐∞) , 3.38 μg·h/mL at 25 mg/kg and darapladib: C max , 0.15 μg/mL; AUC (0‐∞) , 2.11 μg·h/mL at 50 mg/kg).…”

“…Remarkably, oral single doses of 125 mg GSK2647544 resulted in improved PK performance compared with single doses of 160 mg darapladib (area under curve [AUC] (0‐∞) : 2506 ng·h/mL of GSK2647544 vs 645 ng·h/mL of darapladib, ng·h/mL; C max : 457 ng/mL of GSK2647544 vs 18 ng/mL of darapladib, ng/mL). In addition, the inhibition of plasma Lp‐PLA2 activity was dose‐dependent, and 80 mg twice per day (160 mg daily dose) inhibited greater than or equal to 80% of plasma Lp‐PLA2 activity at trough, which is necessary for an enzyme inhibitor to produce a clinical effect . Furthermore, GSK2647544 could likely penetrate into the brains of preclinical species, which was verified by positron emission tomography biodistribution studies using [ 18 F] radiolabeled GSK2647544.…”

“…Among them, GSK2647544 was a potent and specific inhibitor of Lp‐PLA2 disclosed in an early patent . In human subjects, GSK2647544 administration was well tolerated for single oral doses up to 750 mg and displayed no significant adverse events . Remarkably, oral single doses of 125 mg GSK2647544 resulted in improved PK performance compared with single doses of 160 mg darapladib (area under curve [AUC] (0‐∞) : 2506 ng·h/mL of GSK2647544 vs 645 ng·h/mL of darapladib, ng·h/mL; C max : 457 ng/mL of GSK2647544 vs 18 ng/mL of darapladib, ng/mL).…”

“…However, another study reported that GSK2647544 might be a moderate to strong CYP3A4 inhibitor, suggesting potential adverse drug‐drug interaction. This finding led to the early termination of this study . Compounds 19 to 22 are specialized pyrimidine inhibitors with one or two fused heterocycles .…”