A population pharmacokinetic model of intravenous telavancin in healthy individuals to assess tissue exposure
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.
KeywordsTelavancin Population pharmacokinetics Skin and soft tissue infections Probability of target attainment Saturable protein binding Methicillin-resistant Staphylococcus aureus
Author contribution statement
PM and MZ conceived, designed, and conducted the clinical study. SU and MT developed population pharmacokinetic model and performed simulations. MZ and UF supervised the clinical study and population pharmacokinetic analysis respectively. SU wrote initial draft of the manuscript. All authors contributed in and agreed upon the final version of the manuscript.
Financial support in the form of PhD scholarship of Sami Ullah from the Higher Education Commission, Pakistan, through the German Academic Exchange Service (DAAD) is highly acknowledged. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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