Abstract
The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of solubility have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aqueous solutions up to 40 °C. After incubation for 44 h in rat, dog, monkey and human plasma at 37 °C, the percent of CD101 remaining (91%, 79%, 94% and 93%, respectively) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, respectively). Similarly, after incubation in phosphate-buffered saline at 37 °C, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited <2% degradation after long-term storage at 40 °C as a lyophilized powder (9 months) and at room temperature in 5% dextrose (15 months), 0.9% saline (12 months) and sterile water (18 months). Degradation was <7% at 40 °C in acetate and lactate buffers (6 to 9 months at pH 4.5–5.5). The chemical stability and solubility of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. therapy.
Highlights
Candida is the leading cause of bloodstream infections within US hospitals and has been found to account for 22% of inpatient bloodstream infections.[1]
Stability in plasma Chemical degradation marked by cleavage of the cyclic echinocandin core is common to the currently approved echinocandins and occurs in both plasma and buffered solutions, resulting in inactive degradants that are subject to further reaction and degradation.[15,16,17]
The unique chemical stability of CD101 has largely circumvented the main route of elimination that is observed for anidulafungin and is likely a key contributor to the improved pharmacokinetics of CD101, this alone may not entirely explain the long half-life that is observed in vivo across species.[10]
Summary
Candida is the leading cause of bloodstream infections within US hospitals and has been found to account for 22% of inpatient bloodstream infections.[1]. Since 2009, echinocandins have been recommended as first-line therapy against suspected or confirmed candidemia and invasive Candida infections.[2,3] As potent noncompetitive inhibitors of the plasma membrane-bound β-1,3-D-glucan synthase, the echinocandins inhibit the synthesis of β-1,3-D-glucan, a structural polymer that comprises up to 60% of the cell wall of Candida spp.[4] The prevalence of this polymer in certain fungi, the lack of it in mammals, the low incidence of resistance and virtually nonexistent drug interactions make the echinocandins very attractive and the safest of all existing classes of systemic antifungal agents Despite these advantages, the pharmacokinetic and stability properties of the currently approved echinocandins impose limitations on their use. The susceptibility to hydrolytic, thermal and (for micafungin) photodegradation[7] of the approved echinocandins impose limitations for manufacturing, storage, usage and acceptable dosage forms for this otherwise attractive drug class
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
