Pharmacokinetic-Pharmacodynamic Analyses of Dose Selection for Rezafungin Prophylaxis Against Invasive Fungal Infections in Bone Marrow Transplantation

Abstract

Background Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal infections caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. RZF has demonstrated in vivo prophylaxis efficacy and low risk of drug-drug interactions. Furthermore, the stability and PK profile of RZF allow for once-weekly dosing. RZF is also in development for treatment of candidemia and invasive candidiasis using a dosing regimen of RZF 400 mg followed by 200 mg once-weekly, which achieved >90% target attainment against Candida. While lower doses might be useful to prevent Candida and Pneumocystis, invasive aspergillosis is a different challenge. We evaluated RZF dosing for prophylaxis against Aspergillus fumigatus in bone marrow transplant (BMT) patients using PK/PD simulations of the treatment dosing regimen. Methods A previous population PK model was refined using data from Phase 1 and Phase 2 trials of IV RZF (NONMEM Vers 7.2). Stepwise forward selection (α = 0.01) and backward elimination (α = 0.001) were used to assess for relationships between interindividual PK variability and covariates, such as age, sex, BSA), albumin, liver and renal function markers, and infection status. The final model was validated by comparing model-based predictions to observed data. The model and demographic data from BMT recipients at Stanford Medical Center (Table 1) were used for Monte Carlo simulation (n=2,000) of expected RZF concentration-time profiles in BMT patients receiving IV RZF 400 mg on Week 1 followed by 200 mg weekly x 11. Free-drug concentration-time profiles were evaluated (97.4% human protein-binding) relative to the A. fumigatus minimal effective concentration required to inhibit 100% of isolates tested (MEC100; JMI 2014-2017 SENTRY international surveillance data). Results The population PK model was a linear, 4-compartment model with zero order IV input. Albumin was a statistically significant predictor of interindividual variability. Non-significant relationships were found with sex, BSA, presence of cirrhosis, and infection status. The model provided precise, unbiased fits to the observed data (r2=0.993 observed vs individual-predicted). RZF plasma free-drug concentrations at weeks 1, 2, and 12 were above the A. fumigatus MEC100 (0.03 mg/L) for the entire dosing interval in 98.4%, 93.3%, and 91.9% of simulated patients, respectively, and in ≥99.9% for all 12 weeks based on the MEC90 (0.015 mg/L). Conclusions These data modeled from BMT patients support the RZF dosing regimen of 400 mg IV followed by 200 mg once-weekly for prophylaxis against A. fumigatus. Current antifungal prophylaxis may be limited by toxicity, DDIs, or patient factors such as mucositis. The PK of RZF and its spectrum, safety, tolerability, and lack of DDIs may address challenges in IFI prophylaxis for BMT and other immunocompromised patients.