Assessment of oritavancin serum protein binding across species
Abstract number: P1239
Arhin F., Belley A., Sarmiento I., McKay G.A., Parr Jr. T., Moeck G.
Objective: Estimates of serum protein binding are essential to translate drug exposure from nonclinical studies to humans during assessments of toxicology, pharmacokinetics, and pharmacodynamics. Oritavancin is a late-stage investigational lipoglycopeptide under study for treatment of serious Gram-positive infections. Nonspecific binding of oritavancin to plastic, glass, and filtration/dialysis membrane surfaces confounds traditional biophysical methods to assess protein binding. We estimated binding of oritavancin to human, mouse, rat and beagle dog serum from serum-induced increases in minimal inhibitory concentrations (MICs) using arithmetic drug dilutions under conditions that minimize nonspecific binding to labware surfaces.
Methods: Serum ultrafiltrate from each species was prepared using Centricon Plus-50 ultrafilters, whose molecular weight cutoff (50 kDa) excludes serum albumin. Oritavancin, ceftriaxone and daptomycin MICs against Staphylococcus aureus ATCC 29213 were determined by broth microdilution using arithmetic drug dilutions in 95% serum and 95% serum ultrafiltrate (supplemented with 5% cation-adjusted Mueller-Hinton broth) in parallel to assess the impact of serum albumin on their antimicrobial activity. Serum protein binding for each drug was calculated as follows:
% bound = (1 - [MIC in serum ultrafiltrate/MIC in serum])×100%.
Results: Increases in arithmetic oritavancin MIC in serum vs. serum ultrafiltrate, by species, were similar across species (range, 5.5- to 7.8-fold). Such shifts yielded mean values of oritavancin serum binding that were similar for the four species tested (range, 81.9% to 87.1%). Daptomycin binding to serum protein was more variable across species, ranging from 65.6% to 82.9%. Ceftriaxone was highly bound to human serum (92.6%) but substantially less bound to serum from mouse, rat, and beagle dog (range, 20.9% to 37.5%).
Conclusions: The broth microdilution-based method described here allowed for estimation of oritavancin serum protein binding with minimal drug losses to labware vessels. This method would likely be suitable for other drugs exhibiting nonspecific binding to labware surfaces. Oritavancin binding to serum was consistent across the species tested, with serum protein binding values reported here approximating those reported previously for human serum. These values will support translation of oritavancin exposure from nonclinical studies to humans.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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