Pharmacokinetic analyses provide evidence to support once-weekly dosing of rezafungin to prevent Aspergillus fumigatus in bone marrow transplant recipients.
Once-weekly dosing of rezafungin is effective in the prevention of Aspergillosis among patients who had received bone marrow transplants, investigators revealed Saturday in a poster session at the 60th Annual American Society of Hematology Annual Meeting in San Diego, California.
Prevention of invasive A fumigatus is a challenge for clinicians treating immunosuppressed patients, including individuals who have received bone marrow transplants because anti-rejection medications weaken the immune system.
Rezafungin is a novel antifungal of the echinocandin class being developed by Cidara Therapeutics for the prevention of invasive fungal infections caused by Candida, Aspergillus, and Pneumocystis in patients at high risk of infection. Rezafungin has a long half-life—approximately 133 hours—which enables the administration of once-weekly dosing regimens.
To evaluate an appropriate dosing regimen for the echinocandin in the prevention of A fumigatus among bone marrow transplant recipients, a team of investigators conducted pharmacokinetic-pharmacodynamic simulations in which they compared a pharmacokinetic model to observed data.
The investigators refined a previously developed pharmacokinetic population model using intravenous (IV) data from additional phase 1 and phase 2 studies. In the study, the investigators studied the ability of “covariates such as body size, age, albumin, markers of liver and renal function and infection status to explain a portion of the interindividual variability on select Pharmacokinetic parameters … using stepwise forward selection and backward elimination.”
The model was validated by comparison to baseline demographic data that were available from 100 patients who underwent a bone marrow transplant at Stanford Medical Center.
Using the dataset, and the developed population pharmacokinetic model, the investigators conducted a Monte Carlo simulation to explore “expected rezafungin concentration-time profiles” in bone marrow transplant recipients following administration of rezafungin.
The participants received a single dose of 400 mg of rezafungin intravenously at week 1, followed by 200 mg once-weekly for the remaining 11 weeks.
From surveillance data collected in 2016, free-drug concentration-time profiles were evaluated relative to the maximum observed A fumigatus minimal effective concentration (MEC) to inhibit 100% of isolates tested (MEC100) using a human protein-binding value of 97.4%.
In the final population pharmacokinetic model, a linear, 4-compartment model with zero order IV input, the investigators noted that albumin was an important predictor of the interindividual variability, because it was observed that there were relationships between serum albumin concentration and clearance and volume of peripheral compartment.
It was also noted that relationships were observed between the parameters and sex, body surface area, presence of cirrhosis, and infection status.
In the demographic data set, the median baseline body surface areas were 1.84 m2 and the median albumin was 3.35 g/dL. Additionally, there were no patients with infection or cirrhosis at baseline.
The authors wrote that at weeks 1, 2, and 12, 98.4%, 93.3%, and 91.9% of simulated patients, respectively, had rezafungin free-drug concentrations above the MEC100 value for the entire week. And the result was ≥99.9% for all 12 weeks when based on the MEC90 (0.015 mg/L).
The authors of the analyses also indicated that the favorable pharmacokinetic profile of the candidate provides the opportunity to mitigate challenges of the administration of prophylaxis for invasive fungal infections in recipients of bone marrow transplants and other immunocompromised patients.
According to a statement issued by Cidara, the company plans to launch the phase 3 ReSPECT prophylaxis trial evaluating rezafungin in patients undergoing allogenic bone marrow transplants in the first quarter of 2019.