CAVALERI M, COOPER A, NUTLEY MA, STOGNIEW M; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. A-1385.

Biosearch Italia Spa, Gerenzano (VA), Italy.

BACKGROUND: Dalbavancin (DAL) is a semisynthetic glycopeptide antibiotic with activity against Gram-positive bacteria. DAL has a long half-life in man (~ 10 days) and retains bactericidal activity in serum (SBA) for up to 7 days following a single 1 G dose. Determination of the extent and characteristics of DAL plasma protein binding is required to fully understand DAL pharmacokinetics (PK) and pharmacodynamics. Conventional protein binding methods are confounded due to DAL high non-specific binding and precipitation. Isothermal titration microcalorimetry (ITC) is an alternative approach for the determination of protein binding, and was investigated as a method for assessing the protein binding of DAL. METHODS: Binding of DAL to human, bovine, rat, and dog serum albumin, and to human a -1 glycoprotein, was investigated using ITC at 25 degrees C, pH 7.4. Aliquots (10 microL) of a 150 microM protein solution were injected into DAL solutions (4-7 microM, 1.4 mL). RESULTS: Experiments conducted with human serum albumin and a -1 glycoprotein showed exothermic responses consistent with reversible protein-antibiotic binding. The thermal titration data are consistent with 1:1 complex formation and binding affinities (K[a]) of ~ 2-3x10[5] M[-1]. This implies that at physiological concentrations of HSA (5-7x10[-4] M) and a -1 glycoprotein (1-2x10[-5] M), the extent of DAL plasma protein binding is >/= 99% at anticipated DAL therapeutic concentrations. CONCLUSIONS: ITC is a feasible method for the evaluation of DAL protein binding. DAL demonstrates high capacity and low affinity for human plasma proteins. The high capacity helps to explain several PK characteristics of DAL: the relatively high plasma concentrations achieved in spite of poor solubility of the compound at physiologic pH; and the prolonged half-life. The low affinity helps to explain the observed SBA activity, which greatly exceeds what would be expected for a compound with a free fraction of <1%.

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Blood Proteins
• Calorimetry
• Cattle
• Dogs
• Evaluation Studies
• Glycoproteins
• Humans
• Hydrogen-Ion Concentration
• Male
• Protein Binding
• Proteins
• Rats
• Titrimetry
• methods

Other ID:

• GWAIDS0026981

UI: 102266605

From Meeting Abstracts