Kidney Injury Associated with Telavancin Dosing Regimen in an Animal Model

Abstract

The elevation of serum creatinine levels is a concern with telavancin therapy. We examined the onset of kidney injury associated with telavancin in an animal model. Urine samples were collected at baseline and daily to determine the concentrations of kidney injury molecule 1 (KIM-1), a marker for early kidney injury. When a clinically relevant exposure of telavancin was given daily to rats, some differences in kidney injury were attributed to the dosing regimen. Further investigations of alternative telavancin dosing regimens are warranted.T elavancin is a lipoglycopeptide antibiotic which exerts its antibacterial activity by inhibiting peptidoglycan synthesis and causing membrane depolarization (1). In view of its activity against organisms nonsusceptible to vancomycin, daptomycin, or linezolid, it has great potential for use against drug-resistant bacterial infections. Pharmacokinetic-pharmacodynamic studies in an animal infection model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy (2), which suggested that dosing frequency had little influence on antibacterial activity. In the registration trials, all patients randomized to telavancin therapy were given a standard dose of 10 mg/kg of body weight once daily. An elevation in serum creatinine levels was found in an unexpectedly high proportion of the patients (6% to 16%) (3, 4). The impact on these elevations by the dosing frequency is unknown, and the responsible renal histological changes are not well characterized. Our clinical experience suggested that vancomycin nephrotoxicity can be delayed with a nonconventional drug administration schedule (5). The objectives of this study were to (i) investigate the relationship between the pharmacokinetics of telavancin and the onset of kidney injury and (ii) characterize the renal histological changes associated with telavancin in an animal model. Sprague-Dawley CD IGS rats (female, 200 to 250 g; male, 325 to 375 g) were used (Charles River, Raleigh, NC). The jugular veins of the animals were cannulated to facilitate blood sampling. The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Houston. Each animal was given a single telavancin dose of 15 mg/kg, 30 mg/kg, or 60 mg/kg intravenously (n ϭ at least 3 in each group). Six blood samples were obtained from each animal serially (0.5, 1, 2, 4, 6, and 8 h) after the end of drug infusion. The plasma samples were spiked with an internal standard, AMI-13616 (Covance, Princeton, NJ), and assayed for telavancin concentrations by the qualified liquid chromatography tandem mass spectrometry method (6). The assay was linear over the range of 0.0125 g/ml to 250,000 g/ml. The intra-assay and interassay precision levels for the calibration standards were within 10%. The concentrations observed at each time point for each dosing group were averaged, and a pharmacokinetic model was fit to each average concentrationtime profile using ADAPT 5 (University of Southern ...

Time Course and Extent of Renal Function Changes in Patients Receiving Treatment for Staphylococcal Pneumonias: An Analysis Comparing Telavancin and Vancomycin from the ATTAIN Trials

“…Except for day 4, there was no significant difference between treatment groups in shifts of CrCl levels that would have resulted in a telavancin dose modification (CrCl ≤50 ml/min). A similar effect with regard to the time course has been shown in a rat model of nephrotoxicity, in which telavancin was administered at clinically relevant exposures . The study demonstrated that elevations in KIM‐1, a marker of early renal injury, were most pronounced within the first 5 days of therapy, with a peak at about day 3, and then gradually returned to baseline levels.…”

Clinical Pharmacokinetics and Pharmacodynamics of Telavancin Compared with the Other Glycopeptides

“…Indeed, 7.5 mg/kg BW achieved exposure levels in patients with up to moderate renal impairment that were comparable to the standard dose in subjects with normal kidney function, whereas for more severe forms 7.5 mg/kg results in overexposure. Moreover, a number of studies demonstrated that telavancin leads to increases in serum creatinine and exhibits a potential for nephrotoxicity [ 51 – 53 ].…”

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…Telavancin should thus be used with caution in patients predisposed to kidney dysfunction (pre-existing renal disease, diabetes mellitus, congestive heart failure, or hypertension) [10]. Studies in rats suggest that the onset of kidney injury depends on the dose and on the dosing interval (more rapid if a longer dosing interval) [161].…”