Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study

Abstract

Background: The CC-chemokine receptor 4 (CCR4) is thought potentially to play a critical role in asthma pathogenesis due to its ability to recruit type 2 T-helper lymphocytes to the inflamed airways. Therefore, CCR4 provides an excellent target for anti-inflammatory therapy.

Methods: The safety, tolerability, pharmacokinetics and pharmacodynamics of the CCR4 antagonist GSK2239633, N-(3-((3-(5-chlorothiophene-2-sulfonamido)-4-methoxy-1H-indazol-1-yl)methyl)benzyl)-2-hydroxy-2-methylpropanamide, were examined in healthy males. Two studies were performed: 1) an open-label, study in which six subjects received a single intravenous infusion of [14C]-GSK2239633 100 μg (10 kBq) (NCT01086462), and 2) a randomised, double-blind, placebo-controlled, cross-over, ascending dose study in which 24 subjects received single oral doses of GSK2239633 150-1500 mg (NCT01371812).

Results: Following intravenous dosing, plasma GSK2239633 displayed rapid, bi-phasic distribution and slow terminal elimination (t½: 13.5 hours), suggesting that GSK2239633 was a low to moderate clearance drug. Following oral dosing, blood levels of GSK2239633 reached Cmax rapidly (median tmax: 1.0-1.5 hours). Estimated GSK2239633 bioavailability was low with a maximum value determined of only 16%. Food increased GSK2239633 systemic exposure (as assessed by AUC and Cmax). Increases in AUC and Cmax were less than dose proportional. Adverse events were reported by three subjects (50%) following intravenous administration, and by 19 subjects (79%) following oral administration; most (46/47; 98%) events were mild/moderate in intensity. GSK2239633 1500 mg inhibited thymus- and activation-regulated chemokine-induced (TARC) actin polymerisation reaching a mean CCR4 occupancy of 74%.

Conclusion: In conclusion, GSK2239633 was well-tolerated and capable of inhibiting TARC from activating the CCR4 receptor.

Figure 1

Population fits per dose level for pre-dose (Panel A) and 1 hour post-dose (Panel B) in the Single Oral Dose Study. Following single oral dosing of GSK2239633, blood samples were collected from subjects and stimulated with TARC as described. Formation of F-actin was determined following staining with Alexa fluor 647 phalloidin and analysis with a FACSCantoII flow cytometer by measuring the mean Alexa fluor 647 fluorescence intensity of 1,000 cells. The ratio of F-actin formation in CD4⁺ CCR4⁺ and CD4⁺ CCR4^- T-cells was calculated, and the fractional receptor occupancy of CCR4 (Ro) was then determined by estimating a dose-ratio (DR) from the change in effective concentration giving 50% of the maximal response (EC₅₀) of the TARC concentration-response curve before and after dosing with GSK2239633 and using the formula Ro = (DR – 1)/DR.

Figure 2

Thymus- and activation-regulated chemokine-induced increases in F-actin content of CD4⁺ CCR4⁺ T-cells in whole human blood in the absence or presence of GSK2239633 at 1 μM, 3 μM or 10 μM. The data presented are the mean of independent determinations in three donors. Error bars represent standard error of the mean.