Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data

Abstract

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent in vitro activity against Candida albicans and Candida glabrata, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.

Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata

“…The objective of these analyses was to carry out PK-PD target attainment analyses evaluating single-dose and once-weekly rezafungin regimens to provide dose selection support for future clinical studies. These analyses were carried out using a population PK model, nonclinical PK-PD targets for efficacy, and in vitro surveillance data through Monte Carlo simulation ( 23 , 28 , 29 ).…”

“…A previously developed rezafungin population PK model ( 28 ) and nonclinical PK-PD targets for efficacy against C. albicans and C. glabrata ( 29 ) were utilized through Monte Carlo simulation to evaluate percent probabilities of PK-PD target attainment by MIC and overall. The results of these analyses were interpreted in the context of C. albicans and C. glabrata MIC distributions for rezafungin ( 23 ).…”

“…Development of the population PK model utilized to characterize the disposition of rezafungin in plasma was extensively described elsewhere ( 28 ). In brief, data for this model were obtained from two phase 1 studies ( 25 ).…”

Diagnosis and Treatment of Candidemia in the Intensive Care Unit

“…189 Rezafungin (previously CD101; Cidara Therapeutics, Inc.) is a novel long-acting echinocandin characterized by a spectrum of activity that is comparable to the other echinocandins but also a distinct safety PK/PD profile that enables high plasma drug exposure and extended interval dosing. 190,191 In vitro, rezafungin has demonstrated potent activity against a broad range of Candida spp., including echinocandin-and azole-resistant strains, 192 but interlaboratory variation was observed thus warranting further investigation. 193 A multicenter, randomized, double-blind phase 2 trial evaluating the efficacy and safety of rezafungin once weekly compared with caspofungin in patients with candidemia has been recently finished (NCT023734682).…”

Determination of Pharmacodynamic Target Exposures for Rezafungin against Candida tropicalis and Candida dubliniensis in the Neutropenic Mouse Disseminated Candidiasis Model

“…(2,3). The PK of rezafungin in humans has been well characterized (6), including population PK modeling and target attainment analysis for C. albicans and C. glabrata isolates (24,25). According to the highest PK/PD target for each species identified in this study (24-h free-drug AUC/MIC, 15.5 for C. tropicalis and 25 for C. dubliniensis), the target exposure was met or exceeded for C. tropicalis organisms with a rezafungin MIC of Յ0.5 mg/liter and for C. dubliniensis organisms with a rezafungin MIC of Յ0.25 mg/liter.…”