Population pharmacokinetic analysis of intravenous telavancin in healthy subjects undergoing plasma and tissue microdialysis
Sami Ullah (1), Peter Matzneller (2), Markus Zeitlinger (2), Uwe Fuhr (1), Max Taubert (1)
(1) Department of Pharmacology, Hospital of the University of Cologne, Germany (2) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Objectives: Telavancin is a novel lipoglycoprotein used to treat complicated skin and soft tissue infections and hospital acquired pneumonia with MRSA. Non-compartmental analysis of systemic total telavancin concentrations in a microdialysis study gave an average calculated target index (AUC0–24/MIC) slightly below the proposed value [1].
The aim of this additional evaluation of [1] was the development of a compartmental population pharmacokinetic model and its application to evaluate the current standard dosing of 10mg/kg once daily.
Methods: Data was available for eight male healthy subjects (median age and body weight of 27.0 [range 23-35] years and 76.5 [67.0-83.4] kg). A single intravenous infusion of telavancin (10mg/kg within 1 hour) was given to all subjects. Plasma samples and microdialysis samples, representing unbound telavancin concentrations in plasma, muscle and subcutaneous tissue, were taken [1]. Population pharmacokinetic modeling and Monte Carlo simulations were performed using NONMEM VII and Monolix suite 2016R1.
Results: Plasma concentrations of telavancin were best described by a two compartment model with saturable protein binding (Bmax = 81.0 mg/L [25.7%], Kd = 9.36 mg/L [26.7%]). Elimination clearance from the central compartment and inter-compartmental clearance estimates were 1.44 L/h [4.50%] and 2.59 L/h [16.8%]. Central and peripheral volumes of distribution were 6.52 L [10.8%] and 6.08 L [10.0%], respectively. Clearances and volumes were scaled allometrically. Two additional compartments each (interstitial and peripheral) described the distribution into muscle and subcutaneous tissue. For a 10 mg/kg dose, simulations on total plasma concentrations indicated an AUC0–24/MIC of 3497 [range 3140-4008] for a MIC of 0.125 mg/L [2]. The probability of target attainment (PTA) was only 11.6% for the first dose but is expected to approach 100 % at steady state. As simulated AUC0–24/MIC values had low variability and were close to the proposed target AUC0–24/MIC of 3650 [2], PTA may change dramatically with both small changes in exposure and in MIC.
Conclusions: The empirical model was able to describe the data and to provide a new hypothesis on telavancin plasma protein binding in vivo. Further studies are needed to assess whether a slight increase in initial dose (e.g. 12mg/kg instead of 10mg/kg body weight) would result in earlier target achievement and to assess tissue AUC/MIC at steady state.
References:
[1] Matzneller P, Österreicher Z, Reiter B, Lackner E, Stimpfl T, Zeitlinger M. Tissue pharmacokinetics of telavancin in healthy volunteers: a microdialysis study. J Antimicrob Chemother. 2016 Nov;71(11):3179-3184.)
[2] European Committee on antimicrobial susceptibility testing (EUCAST). Consultation on Proposed EUCAST Telavancin Breakpoint Changes, June 2014 http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Consultation/2014/EUCAST_telavancin_breakpoint_consultation_20140602.pdf. Accessed February 26, 2017.
