1694. Coadministration of Rezafungin Does Not Impact the Pharmacokinetics of Cyclosporine, Ibrutinib, Mycophenolate Mofetil, or Venetoclax. (15th December 2022)

• Record Type: Journal Article
• Authors: Flanagan, Shawn; Walker, Helen E; Ong, Voon; Director, Executive; Sandison, Taylor
• Is Part Of: Open forum infectious diseases. Volume 9:(2022)Supplement 2
• Publication Date: 2022-12-15
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofac492.1324
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Rezafungin (RZF) is a novel echinocandin antifungal (Figure 1) in development for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases caused by Candida, Aspergilllus, and Pneumocystis (Figure 2). Vulnerable patient populations may receive antifungal prophylaxis with risks of drug-drug interactions (DDIs) that can alter the pharmacokinetics (PK) of immunosuppressive or anticancer agents. This study was conducted to evaluate the effect of RZF on cyclosporine (CY), mycophenolate mofetil (MM), venetoclax (VX), and ibrutinib (IB). Figure 1. Structure of Rezafungin Figure 2. Rezafungin Phase 3 Program Methods: A Phase 1, open-label study of 32 healthy inpatients (16 males [Group 1], 16 females [Group 2]) was conducted to assess DDIs between RZF (as perpetrator) and CY 200 mg, MM 500 mg (males only), IB 280 mg, or VX 50 mg (females only). Each was given alone and w/ IV RZF (1 h infusion; 400 mg followed by once-weekly 200 mg) with a suitable washout period between dosing (Figure 3). Validated LC-MS/MS methodology was used to determine plasma concentrations of mycophenolic acid, IB, VX and CY. Figure 3. Open-Label, Phase 1, DDI Study Design Results: The PK of all 4 drugs were similar w/ and w/o RZF. Comparison of the exposure (AUC and Cmax) of the drugs given alone or w/ RZF is presented in Table 1. There were no clinically meaningful changes in exposure. Overall, all study drugs were well tolerated. Ten subjects (29.4%) experienced adverse events (AEs) following the administration of the substrate drugs alone and 15 subjects (46.9%) experienced AEs for the substrate drugs w/RZF. There were no deaths or serious adverse events. The most commonly reported AEs were headache and nausea. The majority of AEs were of mild intensity. Two subjects had one severe AE each (abdominal pain related to both RZF and VX and esophagitis related to CY). No trends in safety laboratory results were identified. Table 1. Summary of Statistical Comparisons of Cyclosporine, Mycophenolic Acid, Ibrutinib and Venetoclax Pharmacokinetic Parameters Following Administration of Cylosporine (200 mg), Mycophenolate Mofetil (500 mg), Ibrutinib (280 mg), and Venetoclax (50 mg) alone and in Combination with Rezafungin Conclusion: Once weekly IV administration of RZF w/ single doses of CY, IB, MM and VX did not result in any clinically meaningful change in the exposure of the concomitant medications. No dose adjustments of CY, MM, IB, or VX are expected to be necessary when given in combination w/ RZF. The administration of RZF 400 mg followed by 2 once weekly doses of 200 mg, coadministered w/ CY, IB, and MM or VX, in healthy subjects was considered generally well-tolerated with an acceptable safety profile. Disclosures: Shawn Flanagan, PhD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds Taylor Sandison, MD, MPH, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds.