Aims
The aim of the present study was to investigate whether selective antagonism of the cysteine‐X‐cysteine chemokine receptor‐2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens.
Methods
In a double‐blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte‐colony stimulating factor (G‐CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli.
Results
AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of −1.67 (0.67) ×109 l–1 vs. 0.19 (0.78) ×109 l–1 for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10‐min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G‐CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo‐ and AZD5069‐treated subjects. Superoxide anion production in E. coli‐stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated.
Conclusions
CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.
Controlling the quality of medicines is just as important as demonstrating efficacy. The International Conference on Harmonisation has published general guidance on the quality and safety assessment of impurities in pharmaceutical drug substances and drug products. More recently, the European Medicines Evaluation Agency has published a guideline focusing on limits for genotoxic impurities. This is based on a Threshold of Toxicological Concern (TTC) derived from animal carcinogenicity data using multiple worst case assumptions to estimate a daily dose (1.5 microg/day) associated with a lifetime cancer risk of 1 in 100,000, a risk level considered acceptable for genotoxic impurities in human medicines. Based on these assumptions, presentation of the TTC as a single figure infers an unwarranted level of precision and supports the adoption of a more flexible approach by regulatory authorities when evaluating new drug products; a range within fivefold of the TTC limit would seem sensible. Furthermore, the limit is based on 70 years continuous daily exposure, a scenario that is uncommon for most medicines and irrelevant to the preregistration clinical development phase. To address this latter point, a staged TTC has been developed that proposes limits based on shorter durations of treatment, e.g., up to 1 year. Based on recent history, this approach has been acceptable to some authorities but not to others, and it is imperative that steps are taken to reach a common agreement between the pharmaceutical industry and regulatory authorities globally in order that new medicines can continue to be developed and delivered to benefit patients in a safe and timely manner.
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