Comparison of Pharmacokinetics of Individual Teicoplanin Components in Patients

Abstract

Teicoplanin is a glycopeptide antibiotic currently used for the treatment of a variety of aerobic and anaerobic Grampositive infections, especially those caused by methicillin-resistant Staphylococcus aureus.1) Although the mechanism of action of teicoplanin is very similar to that of vancomycin, its disposition characteristics in the body are quite different. Teicoplanin is a mixture of six major components (molecular weights 1875-1891) with similar chemical structures and polarity and four polar hydrolysis products.1) The antimicrobial activities of these components against certain microbial species differ.2) Pharmacokinetic studies of teicoplanin in healthy volunteers have also shown that the various components differ in their plasma protein binding and volume of distribution. [3][4][5] These pharmacokinetic parameters are correlated with the lipophilicity of the components. 5) However, the clinical utility of selective assays for each component remains unclear.Teicoplanin becomes highly bound to plasma proteins and its volume of distribution (Vss) is greater than 60 l, suggesting that it is affected mainly by protein binding in plasma and tissues, and also tissue volume (Vssϭfub/futϫV t , where fub and fut are unbound fraction in plasma and tissue and V t is tissue volume). Also, the volume of distribution-estimated unbound plasma concentration (Vuss) is affected mainly by tissue binding and tissue volume (Vussϭ1/futϫV t ). On the other hand, teicoplanin is eliminated mainly via renal excretion, and the total clearance of teicoplanin is low, indicating that it is affected mainly by intrinsic clearance (CL int ) and protein binding in plasma (CLϭfupϫCL int ), whereas the clearance estimated from the unbound concentration is affected mainly by CL int . The resulting elimination rate constant is determined mainly by tissue binding, intrinsic clearance and tissue volume. These characteristics indicate the need to determine whether the concentration-time profiles of the individual components are parallel and whether their elimination rate constants differ.In this study, in order to determine whether the pharmacokinetics of the main individual teicoplanin components differ in patients, their concentrations were determined and the population mean pharmacokinetic parameters and unbound fraction were also estimated. MATERIALS AND METHODS Chemicals and ReagentsTeicoplanin sodium (lot. no. 72014765) was kindly provided by Aventis Pharma Ltd. (France). HPLC demonstrated that the authentic sample contained 0.98% A3-1, 3.93% A2-1, 56.4% A2-2, 5.96% A2-3, 13.94% A2-4, and 13.94% A2-5, as reported previously. 6)The concentrations of teicoplanin components in a 1.0 mg/ml concentration of authentic sample were estimated to be 9.8 mg/ml for A3-1, 39.3 mg/ml for A2-1, 564 mg/ml for A2-2, 59.6 mg/ml for A2-3, 139.4 mg/ml for A2-4, and 139.4 mg/ml for A2-5. Acetonitrile and chloroform (both HPLC grade) were obtained from Nacalai Tesque Inc. (Kyoto, Japan).Patient Characteristics Thirty-one patients (23 male, 8 female), who were h...

A multi-centre, phase IV study to evaluate the steady-state plasma concentration and serum bactericidal activity of a generic teicoplanin preparation

“…that there was no clinically significant difference between the individual teicoplanin components in man. 23 These studies support the observations made in the present study.…”

Composition specification of teicoplanin based on its estimated relative bioavailability

“…In the case of glycopeptide antibiotics, slight differences in composition within the range of chemical nature are possible. Although some authors 15 concluded that monitoring the individual components of teicoplanin has no clinical significance on the overall pharmacokinetics, however it has been demonstrated that individual variations imply exposure differences between batches. Those differences are controversial with regard to the microbiological comparability between the generics and the corresponding innovator 19 .…”

“…In addition, the terminal slopes of plasma levels obtained by Bernareggi et al 12 have been extrapolated up to 120 h and thereafter the corresponding AUC 120 0 has been calculated using a trapezoidal rule 17 . Unfortunately, the data of Hanada et al 15 are incomplete and not useful.…”

“…Two of these 12,13 were based on the original analytical method 16 . In the third reference 15 , plasma levels of the first subcomponents were omitted due to some kind of interferences. A compromise solution has been met and the chromatographic results of the references are considered as comparable with the data of the applicants.…”

“…In contrast, Falcoz et al 13 did not publish raw plasma levels, but reported the corresponding AUC 120 0 of each subcomponent in normorenal patients. Hanada et al 14,15 reported a total analytical composition of teicoplanin and a population pharmacokinetic study of A2-2 to A2-5.…”