Sandra Gil-Alonso (1), Nerea Jauregizar (1), Ignacio Ortega (2), Elena Eraso (3) and Guillermo Quindós (3)
(1) Department of Pharmacology, Faculty of Medicine, University of the Basque Country (UPV/EHU), Spain. UFI11/25 “Microbios y Salud”. (2) Research Development and Innovation Department, Faes Farma S.A. Leioa. Spain. (3) Department of Immunology, Microbiology and Parasitology, Faculty of Medicine, University of the Basque Country (UPV/EHU), Spain. UFI11/25 “Microbios y Salud”
Objectives: The importance of the use of echinocandins to treat serious invasive candidiasis is increasing. Duration of the antiinfective activity after drug clears from the site of infection is important, being dose interval selection fundamental [1]. Postantifungal effect (PAFE) is defined as the continuation of suppression of fungal growth after the drug is removed. The aim of this study was to model and characterize the PAFE of anidulafungin against Candida isolates from in vitro static time-kill curve experiments.
Methods: For PAFE studies, Candida albicans and emerging species of Candida cells were exposed to anidulafungin for 1 hour at concentrations ranging from 0.125 to 8 µg/mL depending of the studied species. Afterwards, cell suspensions were washed and re-suspended for drug removal. Samples were taken at each lecture time point (0, 2, 4, 6, 24, 48 hours) and Colony Forming Units per milliliter were determined. Time-kill experiments were done with the same drug concentrations. Data was modeled using NONMEM v.7.2. Diagnostic plots and precision of parameter estimates were evaluated to assess model performance [2].
Results: Time-kill and PAFE data were best fit using and adapted sigmoidal Emax model that corrected for delay in the growth of Candida, delay on the onset of the activity of anidulafungin, steepness of the concentration-response curve, and saturation in the number of Candida. Additionally, a PAFE estimator, defined as the difference in the time required for counts to increase by 1 Log10 between control and after drug removal, was assessed in the mathematical model. PAFE of anidulafungin was generally long and markedly longer for C. albicans than for C. parapsilosis.
Conclusions: The anti-Candida postantifungal effect of anidulafungin can be accurately described using this semi-mechanistic mathematical model. Because of the prolonged PAFE of anidulafungin against C. albicans isolates, less frequent dosing during therapy of those infections could be considered.
References:
[1] Gumbo T. Impact of pharmacodynamics and pharmacokinetics on echinocandin dosing strategies. Curr Opin Infect Dis 2007; 20: 587-91.
[2] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds). NONMEM Users Guides. 1989-2011. Icon Development Solutions. Ellicott City, Maryland, USA.
Reference: PAGE 23 (2014) Abstr 3098 [www.page-meeting.org/?abstract=3098]
Poster: Drug/Disease modeling - Infection