No Relevant Pharmacokinetic (PK) Interaction between Rezafungin and Nine Probe Drugs: Results from a Drug-Drug Interaction (DDI) Study

Abstract

Introduction Rezafungin (RZF) is a new echinocandin being developed to treat patients with systemic fungal infections and to prevent invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients and other patients at high risk of infection. RZF is differentiated by stable and efficacy-driving pharmacokinetics (PK) that allow for once-weekly dosing. Several in vitro studies have been conducted to assess the potential for rezafungin to alter the PK of other drugs. Based on the results, possible interactions were identified in which the risk of drug-drug interactions (DDIs) could not be ruled out relative to the assumed Ph3 dose of 400 mg once weekly and known PK exposure in healthy subjects. Clinical in vivo evaluations of drug interaction potential were performed proactively. Methods This was an open-label, inpatient study of 26 healthy subjects to assess DDIs between RZF and probe drugs selected for known interactions with CYP enzymes and transporters (and consequently commonly used in evaluations of PK interaction), as well as drugs likely to be coadministered with RZF. A loading dose of RZF 600 mg was administered on the first dosing day, to approximate a steady state plasma concentration of multiple once-weekly 400-mg doses, followed by 400-mg doses on days 10 and 15. Probe drugs were administered as part of a cocktail containing ≥2 drugs, once prior to and once after receiving RZF on a schedule designed to allow for washout between doses and to limit interactions with other drugs (Figure 1). Samples were analyzed to determine RZF, tacrolimus, repaglinide, metformin, rosuvastatin, pitavastatin, caffeine, efavirenz, midazolam and digoxin concentrations in plasma (except for tacrolimus which was in whole blood) to characterize the PK profile of each analyte. PK exposure parameters (area under curve [AUC] and maximum concentration [Cmax]) were calculated from the plasma concentration-time profiles by noncompartmental analysis. Results When rezafungin was dosed concomitantly with metformin, pitavastatin, caffeine, efavirenz, midazolam, digoxin, tacrolimus, repaglinide, and rosuvastatin, no relevant change in systemic concentrations of these probe drugs was observed (Figure 2). PK exposure of all drugs were similar with or without RZF. Maximum changes in mean Cmax or AUC were Conclusion No meaningful PK interactions occurred between RZF and the 9 probe drug substrates tested, providing evidence that no RZF dose adjustment is expected when co-administered with these commonly used drugs.