Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults

Abstract

CD101 IV is a novel echinocandin with distinctive pharmacokinetic properties that is being developed as a once-weekly treatment for candidemia and invasive candidiasis. CD101 has potent in vitro activity and in vivo efficacy against a broad range of Candida and Aspergillus species. The primary objective of two randomized, double-blind, placebo-controlled, dose-escalation studies in healthy adults was to determine the safety and tolerability of CD101 IV. Sequential cohorts of 8 subjects (n = 6, active; n = 2, placebo) were administered single (50, 100, 200, 400 mg) or multiple once-weekly (100 mg given once weekly for two weeks [×2], 200 mg ×2, 400 mg ×3) doses of CD101 IV infused over 1 h. There were no deaths, serious adverse events (SAEs), severe adverse events (AEs), or withdrawals from the study due to an AE. The majority of AEs were mild, and all completely resolved. There was a higher incidence of total AEs and mild transient infusion reactions in the 400-mg ×3 dose group. There were no clinically meaningful trends in postbaseline laboratory abnormalities and no safety issues related to electrocardiograms, vital signs, or physical exams. CD101 showed dose-proportional plasma exposures, minor accumulation (30% to 55%), low apparent clearance (<0.28 liter/h), long half-life (t1/2) (>80 h), and minimal urine excretion. CD101 IV was safe and well tolerated at single and multiple doses of up to 400 mg given once weekly for 3 weeks and exhibited a long t1/2, minimal accumulation over several weeks, negligible renal excretion, and high plasma exposures enabling once-weekly dosing.

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy

“…However, comparisons of previous ex vivo studies using the same methods to in vivo CRRT trials of the same drug [16, 17] have shown good agreement in clearance estimates. Our findings of an SC not different from zero in the ex vivo model are very consistent with what is known about the extensive (97–99%) protein binding in humans receiving rezafungin [10]. …”

“…The blood was continuously stirred and heated to 37°C in a water bath during all experiments. Reconstituted rezafungin (Lot number AMU252277; Cidara Therapeutics, San Diego, CA, USA) was added to blood to achieve the final concentration of ~30 mg/L (approximating the plasma peak concentration following multiple once-weekly 400 mg doses [10]). Urea (Lot number 30K0221; Sigma, St. Louis, MO, USA) was used as a control and added to the blood to produce a blood urea nitrogen concentration of ~75 mg/dL.…”

“…Its high plasma protein binding (~97–99%) suggests that rezafungin would be poorly removed by RRT [10]. However, there is a potential for some transmembrane clearance (CL TM ) with contemporary hemodiafilters due to its relatively small volume of distribution (35 L) and molecular weight (1,285 Da).…”

Pharmacokinetics of the Novel Echinocandin CD101 in Multiple Animal Species

“…The half-life of CD101 in human is about 3-fold longer (about 90 h) than that of anidulafungin (about 30 h) (10). It should be noted that 90 h is the effective half-life of CD101 (i.e., the half-life that covers the majority of the AUC), with a longer, later-phase half-life evident at lower concentrations beyond the first week after dosing.…”

“…Unlike currently approved once-daily, IV-only echinocandins, CD101 is highly stable, enabling additional formulations and potential uses. In preclinical and phase 1 studies conducted to date, CD101 has demonstrated distinctive PK characteristics, notably the ability to safely achieve high plasma concentrations and an exceptionally long half-life ( t 1/2 ) (9, 10). …”