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

Abstract

BackgroundExcessive 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.ResultsThere 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.ConclusionThe 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 registrationClinicalTrials.gov identifiers: NCT01209052 and NCT01209104

Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2

“…In human blood, the pIC 50 of 6.4 in the CD11b assay compared with the more potent values seen in binding or functional assays in purified systems is consistent with the moderately high protein binding observed with danirixin (98% in human plasma). This value is also consistent with the pIC 50 of 6.8 (69 ng/ml) determined by pharmacokinetic/pharmacodynamic modeling in phase 1 (Miller et al, 2015).…”

“…The role of CXCR2 antagonists in altering blood neutrophil levels has been investigated since the first reports of neutropenia in human subjects treated with navirixin (Rennard et al, 2015) or AZD5069 (Kirsten et al, 2015). Neutropenia was not observed either preclinically as described here for danirixin or clinically with either danirixin (Miller et al, 2015) or the related compound elubrixin (Lazaar et al, 2011). The differences in the behavior of these compounds at the CXCR2 receptor, as well as selectivity with respect to CXCR1, may explain the distinct clinical observations.…”

“…Hematological effects of danirixin in the clinic have previously been described (Miller et al, 2015). In contrast to danirixin, CXCR2 antagonists from other chemical classes Fig.…”

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Food Effect of Danirixin Hydrobromide Tablets in Japanese Healthy Elderly Participants

“…The dose proportionality following the single oral and intravenous administration of the free base of danirixin has been established in previous studies. 7,10 This study also demonstrated the dose proportionality of danirixin HBr in line with the previous studies. In 1 earlier study, compared to danirixin free base, the HBr salt form of danirixin showed less variability in the PK in spite of higher exposures (92% increase in AUC 0-t and 76% increase in C max ).…”

Blocking inflammation on the way: Rationale for CXCR2 antagonists for the treatment of COVID-19

“…The most developed ones, AZD5069 (AstraZeneca), navirixin (Merck Sharpe & Dohme), danixirin (Glaxo-SmithKline), and the combined CXCR1/ 2 inhibitor reparixin (Dompé Farmaceutici S.p.A.) have completed phase I and II studies. Importantly, they displayed beneficial safety profiles without increasing risk of infection (Roberts et al, 2019;Lazaar et al, 2011;Hastrup et al, 2015;Miller et al, 2015). Studies with ozone-or LPS-induced airway inflammation in human volunteers showed that treatment with CXCR2 antagonists reduced neutrophil counts in the lungs by 50-80% (Lazaar et al, 2011;Leaker et al, 2013).…”