Objective: Calcineurin inhibitors (CNIs) are standard prophylaxis for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Given their narrow therapeutic window and variable bioavailability, rigorous therapeutic drug monitoring is mandatory, particularly during serious infections. Eravacycline, a novel synthetic tetracycline, shares the Cytochrome P450 3A4 (CYP3A4) metabolic pathway with CNIs, yet comprehensive data on their potential pharmacokinetic interactions are scarce. Therefore, this study aimed to evaluate the drug-drug interactions between eravacycline and CNIs, as well as its anti-infective efficacy and safety in allo-HSCT.

Methods: This single-center, retrospective study was conducted at the Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences from August 2023 to July 2025, enrolling allo-HSCT recipients who received CNIs and eravacycline (50 mg IV every 12 hours). CNI concentration-to-dose (C/D) ratios were monitored at a median interval of every 3 days before, during, and after eravacycline administration, with mean C/D ratios calculated for each phase. The primary endpoint was the change in CNI C/D ratios. Secondary endpoints were the anti-infective efficacy and safety of eravacycline.

Results: A total of 44 patients were included, with 30 receiving cyclosporine and 14 receiving tacrolimus. Of the patients, 72.7% (32/44) received eravacycline prior to neutrophil engraftment, while 6.8% (3/44) were treated during aGVHD phase. 36.4% (16/44) once experienced infections during the conditioning phase, with a median treatment duration of 11 days (IQR: 7-15). Primary infection sites were pulmonary (36.4%, 16/44) and bloodstream (27.3%, 12/44), with Stenotrophomonas maltophilia (38.6%, 17/44) as predominant pathogens.

In the cyclosporine group (n=30), C/D ratios increased by 13.5% during eravacycline administration (P=0.012), requiring an 11.1% dose reduction to maintain the therapeutic window. Additionally, C/D ratios rose by 8.0% within five half-lives (5 days) versus the administration phase (P=0.003), necessitating a 6.0% dose reduction. After discontinuation, C/D ratios increased by 37.1% compared to eravacycline administration phase (P=0.001) and by 26.9% compared to five half-lives (P=0.004), requiring dose reductions of 25% and 20%, respectively. In the tacrolimus group (n=14), C/D ratios increased by 62.2% during eravacycline administration (P=0.019), requiring a 40% dose reduction, with no significant changes post-discontinuation (P=0.754). These trends persisted in patients with normal liver and kidney function. Subgroup analysis revealed that when co-administered azoles and letermovir, no significant changes in C/D ratio were observed between pre-treatment and during treatment both in cyclosporine group (n=18) and tacrolimus group (n=7). Molecular docking analysis indicated that eravacycline exhibited a higher affinity for CYP3A4 (binding energy: -9.125 kcal/mol) than CNIs, interacting via hydrogen bonds with the heme in the active site, exerting a more pronounced inhibitory effect on cyclosporine.

Regarding clinical efficacy, the infection-related mortality rate was 4.5% (2/44), with a clinical remission rate of 84.1% (37/44). During treatment, 22.7% (10/44) of patients experienced mild adverse events, including diarrhea, hypertension, and nausea. Drug-related hepatic and renal toxicities occurred in 13.6% (6/44) and 20.5% (9/44) , respectively. The cumulative incidence of aGVHD within 100 days post-eravacycline treatment was 34.1% (95% CI: 20.0%-48.8%).

Conclusion: This study presented the first clinical evidence of drug-drug interaction between eravacycline with CNIs in allo-HSCT, characterized by increased CNI exposure during eravacycline administration and delayed post-cessation exposure elevation. Intensified CNI monitoring and stepwise dose adjustments are recommended throughout and after eravacycline therapy.

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2025
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