Modeling the permeability of Fosfomycin into Abscess Fluid
Maria C. Kjellsson(1), Steven Kern(1,2), Robert Sauermann(3), Veronique Dartois (4), Goonaseelan (Colin) Pillai(1)
1. Novartis Pharma AG, Modeling & Simulation, Basel; Switzerland; 2. University of Utah, Salt Lake City, UT, USA; 3. Medizinische Universität Wien, Universitätsklinik für Klinische Pharmakologie, Wien, Austria; 4. Novartis Institute of Tropical Diseases Pte Ltd, Clinical Pharmacology, Singapore
Background: Most drugs do not exert their effect in plasma, where concentrations generally are measured, but in a defined target tissue which the drug must reach in concentrations high enough to have the desired effect. Target site concentrations are seldom identical to plasma concentrations and may also vary greatly depending on where in the body the target tissue is located. For the treatment of abscesses using anti-infectious drugs the penetration of the drug into the abscess is crucial, although oftentimes unknown, and highly variable depending on location and size of the abscess. Understanding any differential penetration in diseases such as tuberculosis may help understand treatment failures and/or suggest alternate therapeutic strategies. In tuberculosis, it has been suggested that lesion diversity in size, location, structure and cellular/acellular content may contribute to the long treatment duration, treatment failure and the development of drug resistance.
Objective: To investigate the permeability of fosfomycin, a broad spectrum antibiotic, into abscess fluid and investigate how the size and location of abscess may affect the permeability. This is as a broader objective to study the penetration of drugs into tuberculosis lesions.
Methods and data: The data used for this analysis have previously been published using a non-mixed effect modeling approach (1). Patients (n=12) scheduled for abscess drainage were administered an intravenous dose of 8 g fosfomycin at different time points before their surgery. Repeated plasma concentration measurements were made and one concentration measurement in the drained pus was available. In the model-based analysis, the PK was described using a three compartment model with one of the peripheral compartments being the target site. All analyses were conducted using non-linear mixed effects modeling in NONMEM.
Results and conclusions: The previously reported high inter-individual variability (IIV) in the permeability of the drug into the abscess (1) was quantified. The impact of covariates such as abscess size and location to explain fosfomycin PK variability and drug penetration into abscess lesions was investigated and was shown to explain some of the IIV but will be reported in more detail in the poster.
Reference:
[1] Sauermann et al, Antimicro. Agents Chemother. 49(11), 2005
