ABSTRACT
Background: SHR8554 is a novel µ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects. Methods: A single 1 mg/41.3 µCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatography-tandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection. Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216 h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed. Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20220450.
ABSTRACT
Background: Whether nebulized polymyxin B should be used as an adjunctive therapy or substitution strategy to intravenous polymyxin B for the treatment of ventilator-associated pneumonia (VAP) remains controversial. This study's aim is to evaluate the efficacy and safety of different administration ways of polymyxin B in the treatment of ventilator-associated pneumonia caused by extensively drug-resistant Gram-negative bacteria(XDR-GNB). Methods: This retrospective cohort study enrolled ventilator-associated pneumonia patients caused by XDR-GNB treated with polymyxin B in the intensive care unit. Patients were categorized by the administration methods as intravenous (IV) group, inhaled (IH) group, and the intravenous combined with inhaled (IV + IH) group. Microbiological outcome and clinical outcome were compared in each group. The side effects were also explored. Results: A total of 111 patients were enrolled and there was no difference in demographic and clinical characteristics among the three groups. In terms of efficacy, clinical cure or improvement was achieved in 21 patients (55.3%) in the intravenous group, 19 patients (50%) in the IH group, and 20 patients (57.1%) in IV + IH group (p = 0.815). All three groups showed high success rates in microbiological eradication, as 29 patients with negative cultures after medication in inhaled group. Among all the patients who had negative bacterial cultures after polymyxin B, the inhaled group had significantly shorter clearance time than the intravenous group (p = 0.002), but with no significant difference in 28-day mortality. Compared with intravenous group, a trend towards a lower risk of acute kidney injury was observed in inhaled group (p = 0.025). Conclusion: From the perspective of minimal systemic renal toxicity, nebulized polymyxin B as a substitution strategy to intravenous polymyxin B for the treatment of ventilator-associated pneumonia caused by XDR-GNB is feasible.
