Mass Balance and Pharmacokinetics of [14C]Telavancin following Intravenous Administration to Healthy Male Volunteers

The mass balance and pharmacokinetics of telavancin, a semisynthetic lipoglycopeptide antimicrobial agent, were characterized in an open-label, phase 1 study of six healthy male subjects. After a single 1-h intravenous infusion of 10 mg/kg [¹⁴C]telavancin (0.68 μCi/kg), blood, urine, and feces were collected at regular intervals up to 216 h postdose. Whole blood, plasma, urine, and fecal samples were assayed for total radioactivity using scintillation counting; plasma and urine were also assayed for parent drug and metabolites using liquid chromatography with tandem mass spectrometry. The concentration-time profiles for telavancin and total radioactivity in plasma were comparable from 0 to 24 h after the study drug administration. Telavancin accounted for >95% and 83% of total radioactivity in plasma at 12 h and 24 h, respectively. By 216 h, approximately 76% of the total administered dose was recovered in urine while only 1% was collected in feces. Unchanged telavancin accounted for most (83%) of the eliminated dose. Telavancin metabolite THRX-651540 along with two other hydroxylated metabolites (designated M1 and M2) accounted for the remaining radioactivity recovered from urine. The mean concentrations of total radioactivity in whole blood were lower than the concentration observed in plasma, and mean concentrations of THRX-651540 in plasma were minimal relative to mean plasma telavancin concentrations. These observations demonstrate that most of an administered telavancin dose is eliminated unchanged via the kidneys. Intravenous telavancin at 10 mg/kg was well tolerated by all subjects.Telavancin is a once-daily injectable, semisynthetic lipoglycopeptide antibiotic with bactericidal activity in vitro against a broad spectrum of clinically important Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), streptococci, and enterococci (4, 5, 9, 10). Telavancin has a dual mode of action, involving inhibition of bacterial cell wall peptidoglycan biosynthesis and disruption of bacterial cell membrane functional integrity (7). In phase 3 trials, telavancin was shown to be noninferior to conventional vancomycin therapy for treatment of complicated skin and skin-structure infections (cSSSIs) and nosocomial pneumonia caused by Gram-positive bacteria and demonstrated an acceptable safety and tolerability profile (13, 15, 16). Telavancin is indicated in the United States and Canada for the treatment of adult patients with cSSSI caused by susceptible Gram-positive bacteria and is under investigation for the treatment of Gram-positive nosocomial pneumonia.Single- and multiple-dose pharmacokinetic parameters for telavancin have been evaluated in phase 1 studies, in which telavancin displayed linear and time-invariant pharmacokinetics following intravenous administration (6, 14, 17). Since telavancin is largely excreted intact in urine along with small amounts of its primary hydroxylated metabolite THRX-651540 (data on file with Theravance, Inc., South San Francisco, CA), renal clearance is thought to be the major route of elimination. The objectives of the present study were to confirm this hypothesis by characterizing the mass balance and pharmacokinetics of single-dose [¹⁴C]telavancin in human subjects.