Universität zu Köln

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

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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
Creators:	Creators Email ORCID ORCID Put Code Ullah, Sami UNSPECIFIED orcid.org/0000-0003-1891-4524 UNSPECIFIED Matzneller, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeitlinger, Markus UNSPECIFIED orcid.org/0000-0002-1873-3953 UNSPECIFIED Fuhr, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, Max UNSPECIFIED orcid.org/0000-0001-8925-7782 UNSPECIFIED
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
Uncontrolled Keywords:	Keywords Language PROTEIN-BINDING; MICRODIALYSIS; PENETRATION; PHARMACODYNAMICS; DAPTOMYCIN Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14356