In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Target Characterization of the Novel, Long Acting Echinocandin CD101 against C. albicans and C. glabrata in the Neutropenic Murine Disseminated Candidiasis Model

Abstract

BackgroundCD101 is a novel, long acting echinocandin. The purpose of the study was to evaluate the PK/PD activity of CD101 against C. albicans (CA) and C. glabrata (CG) using the murine neutropenic disseminated candidiasis model.Methods4 CA and 3 CG strains were used. MICs were determined by CLSI standards. Single dose plasma PK was determined in groups of three mice after IP doses of 1, 4, 16, and 64 mg/kg. For treatment studies, mice were rendered neutropenic via administration of cyclophosphamide at days -4, -1, +2 and +4. Mice were infected with 6.3 ± 0.1 CFU/mL (CA) or 6.2 ± 0.2 CFU/mL (CG) injected into the lateral tail vein. Treatment dose range was 0.016 – 64 mg/kg, given once by IP injection 2 hours after infection. Experiment duration was 7 days at which point kidneys were aseptically harvested for CFU counts. The Emax Hill equation was used to model the dose–response data to PK/PD index AUC/MIC. The static and 1-log kill doses, as well as associated total and free AUC/MIC values were determined for each isolate.ResultsCD101 MICs were 0.008–0.06 mg/L for CA and 0.06 – 0.5 mg/L for CG. Single dose plasma PK parameter ranges include: Cmax 2.6–77 mg/L, AUC0-∞ 93–4046 mg*hours/L, T1/2 28–41 hours. Dose-dependent cidal activity was observed with a maximal kill of over 2 log10 CFU/kidney. Average 24 hours AUC over 7 days was used to model AUC/MIC data and fit the treatment response data well (CA R2 0.70, CG R2 0.86). The static dose (SD) and 1-log kill dose and associated total and free AUC/MIC values are shown (Table).StrainMIC (mg/L)Static Dose (mg/kg)Stasis Ave 24 hours tAUC/MICStasis Ave 24 hours fAUC/MIC1 log kill dose (mg/kg)1 log kill Ave 24 hours tAUC/MIC1 log kill Ave 24 hours fAUC/MICCAK-10.0082.52342644.55.26643583.65800.0161.2094812.32.03142918.698–170.061.342743.62.734906.498–2100.0161.0686811.32.28157420.5CG109560.56.291201.617.33013.955920.060.0321.70.30.511141.5353150.250.3417.90.22.391051.4ConclusionCD101 demonstrated in vivo potency in the neutropenic murine disseminated candidiasis model against select CA and CG strains. Similar to studies with other echinocandins, AUC/MIC fit the exposure-response data well and CG targets were numerically lower than CA. However, while CA target range was similar, CG target range was almost 10-fold lower compared with other echinocandins.Disclosures B. Vanscoy, Cidara: Research Contractor, Research support; P. G. Ambrose, Cidara: Research Contractor, Research support; D. R. Andes, Cidara: Grant Investigator, Research support