Teicoplanin binding in plasma following administration of increasing intravenous doses to healthy volunteers.

Teicoplanin is a new long half-life glycopeptide antibiotic active against Gram-positive bacteria. Binding to plasma protein can significantly affect the pharmacokinetics of drugs with low extraction ratio, such as teicoplanin; clearance, volume of distribution and half-life of the drug change as the fraction of drug unbound (fu) varies, with obvious clinical implications. In this study, the linearity of teicoplanin binding to plasma protein was studied in healthy volunteers receiving single increasing intravenous doses of 15, 20 and 25 mg/Kg teicoplanin. Unbound fraction of teicoplanin in human plasma was determined by ultrafiltration. Unbound and total teicoplanin concentrations, Cu and Cp, were measured by microbiological assay. The results indicate that Cu was linearly correlated to Cp in the Cp range from 7 to 280 mg/L, according to the following regression model: Cu = 0.105 Cp - 0.234 (r = 0.9947) in which the coefficient 0.105 represents the average fu. Individual estimates of fu were calculated for every sample as the ratio between Cu and Cp; mean fu values were 0.100 +/- 0.002 (SE), 0.101 +/- 0.002 and 0.097 +/- 0.002, after 15, 20 and 25 mg/Kg, respectively. No statistical difference was found between groups. We conclude that the binding of teicoplanin to plasma protein is linear up to about 300 mg/L and fu value is not dose-dependent from 15 to 25 mg/Kg dose. These conclusions are in keeping with the observation that the pharmacokinetics of teicoplanin is linear in the dose range from 15 to 25 mg/Kg. These estimates of teicoplanin unbound fraction using ultrafiltration are also in agreement with previously reported values obtained by equilibrium dialysis. A mathematical model is proposed to predict changes of fu as the total plasma concentration increases.