The pharmacokinetics and pharmacodynamics of danirixin (GSK1325756)--a selective CXCR2 antagonist --in healthy adult subjects

Abstract

Background: Excessive neutrophil presence and activation is important in a number of acute and chronic inflammatory diseases. The CXCR2 chemokine receptor is important in controlling the extravasation and activation of neutrophils. Selective antagonism of the CXCR2 receptor is a potential approach to reducing neutrophil migration and activation. Danirixin, is a small molecule, CXCR2 antagonist being evaluated as a potential anti-inflammatory medicine.

Methods: (1) First time in human (FTIH) double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and pharmacodynamics of single ascending and repeat oral doses of danirixin in healthy male subjects; (2) single-dose study of age, gender, food, and proton-pump inhibitor effects on the pharmacokinetics of danirixin in healthy adult subjects; and placebo-controlled study of the pharmacokinetics of danirixin in healthy elderly subjects.

Results: There were no serious adverse events and no adverse events considered to be of clinical relevance. There were no withdrawals due to adverse events. Systemic exposure following single doses of danirixin 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg increased with increasing dose. Engagement of pharmacology was demonstrated as inhibition of ex-vivo CXCL1-induced CD11b expression on peripheral blood neutrophils when compared to placebo (approximately 50% for 50 mg and 100 mg danirixin, and 72% at 200 mg). There was a 37% decrease in Cmax and a 16% decrease in AUC (0-∞) following administration of danirixin in the presence of food. Cmax also decreased by 65% when danirixin 100 mg was administered following omeprazole 40 mg once daily for 5 days. The AUC (0-∞) and Cmax were 50% lower in elderly subjects compared with younger subjects.

Conclusion: The dose-dependent inhibition of agonist-induced neutrophil activation following single and repeated once daily oral administration of danirixin suggests that this CXCR2 antagonist may have benefit in neutrophil-predominant inflammatory diseases. Co-administration with food, gastric acid reducing agents, and variable exposure in the elderly have important clinical implications that need to be taken into consideration in subsequent clinical evaluations.

Trial registration: ClinicalTrials.gov identifiers: NCT01209052 and NCT01209104.

Figures

Fig. 1

Danirixin Free Base

Fig. 2

Study design algorithm for Study 1 (FTIH)

Fig. 3

Study design algorithm for Study 2 (Fed versus Fasted, Elderly, Omeprazole Interaction)

Fig. 4

Plot of individual subject danirixin blood dose-normalized AUC (A) and Cmax (B) versus dose for cohorts 1, 2, and 5 in Study 1 (FTIH). The geometric means (with 90 % confidence intervals) are also shown

Fig. 5

Adjusted geometric means of ratio to baseline ex vivo CXCL-induced CD11b expression (0–24 h) versus time for single dose Study 1 (FTIH): fractional increase from control (CXCL1 0 nM) with 95 % CIs

Fig. 6

Plot of inhibition of ex vivo CXCL1-induced CD11b expression versus whole blood concentration of danirixin for Study 1. The plot shows all timepoints where results are available for both danirixin whole blood concentration and ex vivo CXCL1-induced CD11b expression

Fig. 7

Mean pharmacokinetics concentration plot versus time for Study 2 (Fed versus Fasted, Elderly, Omeprazole Interaction)