Absence of Clinically Meaningful Drug-Drug Interactions with Rezafungin: Outcome of Investigations

ABSTRACT Rezafungin is a novel once-weekly echinocandin for intravenous injection currently in development for the treatment of Candida infections and the prevention of Candida, Aspergillus, and Pneumocystis infections in allogeneic blood and marrow transplant recipients. While in vitro data indicated that rezafungin exposure was unlikely to be affected by commonly prescribed medicines, interactions resulting in the altered systemic exposure of some drugs coadministered with rezafungin could not be excluded. Two phase 1 open label crossover studies, conducted in healthy subjects, examined drug interactions between rezafungin and multiple drug probe cytochrome P450 (CYP) substrates and/or transporter proteins, immunosuppressants, and cancer therapies. Statistical analysis compared the outcomes for drugs coadministered with rezafungin to those for the drugs administered alone. The geometric mean ratio was reported, and a default 90% confidence interval (CI) no-effect equivalence range of 80 to 125% was used for the maximal plasma concentration (Cmax), the area under the curve from time zero to the final sampling time point (AUC0–t), and the AUC from time zero to infinity (AUC0–∞). Most probes and concomitant drugs were within the equivalence range. For tacrolimus, ibrutinib, mycophenolic acid, and venetoclax, the AUC or Cmax was reduced (10 to 19%), with lower bounds of the 90% CI values falling outside the no-effect range. The rosuvastatin AUC and Cmax and the repaglinide AUC0–∞ were increased (12 to 16%), with the 90% CI being marginally above the upper bound. Overall, the in vitro and in vivo data demonstrated a low drug interaction potential with rezafungin via CYP substrate/transporter pathways and commonly prescribed comedications, suggesting that coadministration was unlikely to result in clinically significant effects. Treatment-emergent adverse events were typically mild, and rezafungin was generally well tolerated. IMPORTANCE Antifungal agents used to treat life-threatening infections are often associated with severe drug-drug interactions (DDIs) that may limit their usefulness. Rezafungin, a newly approved once-weekly echinocandin, has been shown to be free of DDIs based on extensive nonclinical and clinical testing described in this study.

0 Abbreviations: TEAE = Treatment emergent adverse event. Safety Population = all subjects who receive any amount of study drug; Rezafungin Safety Population = all subjects who receive any amount of rezafungin for injection; each TEAE is counted only once for each subject within each System Organ Class and Preferred Term by using the adverse events with the highest intensity within each category.

NC-049
Membrane permeability and P-gp and/or BCRP substrate potential of rezafungin was assessed using Caco-2 epithelial monolayers expressing human P-gp and BCRP.
Permeability of rezafungin was very poor (permeability coefficient <0.2 x 10-6 cm/s) in both transport directions in the absence and presence of inhibitors. It was concluded that active transport was likely not to be involved and rezafungin was not a substrate of P-gp or BCRP.

NC-052
A study to determine if rezafungin is a substrate of human OATP1B1 and OATP1B3 transporters in transiently transfected HEK293 cells.
Rezafungin was determined not to be a substrate of OATP1B1 or OATP1B3 (uptake ratio <2).

NC-152
A study to assess the potential of rezafungin as an inhibitor of the human transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, OCT1, MATE1 and MATE2-K in various in vitro cell test systems, and of BSEP in membrane vesicles.

NC-160
Evaluation of in vitro substrate interactions of rezafungin with BCRP, MDR1, and MRP2 Efflux (ABC) and OCT1, OCTN1, and OCTN2 uptake SLC transporter as well as the inhibition of rezafungin with BCRP using membrane vesicle preparations.

NC-013
Follow-up CYP450 inhibition study in human liver microsomes to further examine the potential for rezafungin to inhibit the activity of CYP isoforms 2C8 and 3A4.

NC-153
Study to determine whether rezafungin is a time dependent inhibitor of the CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 (midazolam and testosterone as substrates) in human liver microsomes.
No evidence of CYP induction (as measured by <2-fold increase in mRNA expression) of CYP1A2 and CYP2B6, and, in the case of CYP3A4, in 2 of 3 donors. More specifically, for CYP3A4, only 1 out of the 3 donors tested showed a 2.68-fold induction of mRNA expression at the highest feasible concentration (3 µM) tested.