Ullah, Sami ORCID: 0000-0003-1891-4524, Matzneller, Peter, Zeitlinger, Markus ORCID: 0000-0002-1873-3953, Fuhr, Uwe and Taubert, Max ORCID: 0000-0001-8925-7782 (2019). A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure. Naunyn-Schmiedebergs Arch. Pharmacol., 392 (9). S. 1097 - 1107. NEW YORK: SPRINGER. ISSN 1432-1912
Full text not available from this repository.Abstract
Non-compartmental analysis of telavancin microdialysis data indicated a sustained exposure in soft tissues and that unbound plasma concentrations were underestimated in vitro. The objective of the present evaluation was to develop a population pharmacokinetic model of telavancin to describe its plasma protein binding, its distribution into muscle, and subcutaneous tissue and to predict pharmacokinetic/-dynamic target attainment (PTA). Total plasma concentrations and microdialysate concentrations (plasma, subcutaneous, and muscle tissue) were available up to 24 h (plasma microdialysate, up to 8 h) post-dose from eight healthy subjects after a single intravenous infusion of 10 mg/kg telavancin. Population pharmacokinetic modeling and simulations were performed using NONMEM. A two-compartment model with saturable protein binding best described plasma concentrations. Plasma unbound fractions at steady state were 23, 15, and 11% at 100, 50, and 10% of the maximum predicted concentrations respectively. Distribution into muscle and subcutaneous tissue was non-linear and described appropriately by one additional compartment each. Based on total plasma concentrations, predicted median (95% confidence interval) values of AUC/MIC (MIC 0.125 mg/L, clinical breakpoint for MRSA) at steady state were 4009 [3421-4619] with a PTA of 96 [78-100] %. The fAUC/MIC in muscle was 496 [227-1232] with a PTA of 100 [98-100] %. The %fT(>MIC) was approximately 100% in plasma and interstitial space fluid of muscle and subcutaneous tissues up to an MIC of 0.25 mg/L. The model provided a new hypothesis on telavancin plasma protein binding in vivo. Proposed pharmacodynamic targets in plasma and muscle are achieved with currently approved doses of 10 mg/kg daily.
Item Type: | Journal Article | ||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-143562 | ||||||||||||||||||||||||
DOI: | 10.1007/s00210-019-01647-w | ||||||||||||||||||||||||
Journal or Publication Title: | Naunyn-Schmiedebergs Arch. Pharmacol. | ||||||||||||||||||||||||
Volume: | 392 | ||||||||||||||||||||||||
Number: | 9 | ||||||||||||||||||||||||
Page Range: | S. 1097 - 1107 | ||||||||||||||||||||||||
Date: | 2019 | ||||||||||||||||||||||||
Publisher: | SPRINGER | ||||||||||||||||||||||||
Place of Publication: | NEW YORK | ||||||||||||||||||||||||
ISSN: | 1432-1912 | ||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||
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Refereed: | Yes | ||||||||||||||||||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/14356 |
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