Chemical formula: C₈₀H₁₀₆Cl₂N₁₁O₂₇P Molecular mass: 1,755.65 g/mol PubChem compound: 3081362
Telavancin is an antibacterial drug. It is a semisynthetic, lipoglycopeptide antibiotic. Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive organisms in vitro, as demonstrated by time-kill assays and MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. In vitro studies demonstrated a telavancin post-antibiotic effect ranging from 1 to 6 hours against S. aureus and other Grampositive pathogens.
Telavancin inhibits cell wall biosynthesis by binding to late-stage peptidoglycan precursors, including lipid II. Telavancin also binds to the bacterial membrane and disrupts membrane barrier function.
The antimicrobial activity of telavancin appears to best correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. Exposure-response analyses of the clinical trials support the dose of 10 mg/kg every 24 hours.
The effect of telavancin on cardiac repolarization was assessed in a randomized, double-blind, multiple-dose, positive-controlled, and placebo-controlled, parallel study (n=160). Healthy subjects received telavancin 7.5 mg/kg, telavancin 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from telavancin 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebocorrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for telavancin 10 mg/kg and 22 msec for the positive control (Table). By 1 hour after infusion the maximum QTc prolongation was 6-9 msec for telavancin and 15 msec for the positive control.
Mean and Maximum QTcF Changes from Baseline Relative to Placebo:
| QTcF1 Change from Baseline | ||
|---|---|---|
| Mean (Upper 90% Confidence Limit2) msec | Maximum (Upper 90% Confidence Limit) msec | |
| Telavancin 7.5 mg/kg | 4.1 (7) | 11.6 (16) |
| Telavancin 15 mg/kg | 4.6 (8) | 15.1 (20) |
| Positive Control | 9.5 (13) | 21.6 (26) |
1 Fridericia corrected; 2Upper Confidence Limit (CL) from a 2-sided 90% Confidence Interval (CI) on difference from placebo (msec)
ECGs were performed prior to and during the treatment period in patients receiving telavancin 10 mg/kg in 3 cSSSI studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with telavancin and 164 of 1033 (16%) allocated to vancomycin received concomitant medications known to prolong the QTc interval and known to be associated with definite or possible risk of torsades de pointes. The incidence of QTc prolongation >60 msec was 1.5% (15 patients) in the telavancin group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 telavancin patients received concomitant medications known to prolong the QTc interval and definitely or possibly associated with a risk of torsades de pointes, compared with 1 of the 6 patients who received vancomycin. A similar number of patients in each treatment group (<1%) who did not receive a concomitant medication known to prolong the QTc interval experienced a prolongation >60 msec from baseline. In a separate analysis, 1 patient in the telavancin group and 2 patients in the vancomycin group experienced QTc >500 msec. No cardiac adverse events were ascribed to prolongation of the QTc interval. In the Phase 3 HABP/VABP studies, the incidence of QTc prolongation >60 msec or mean value >500 msec was 8% (52 patients) in the telavancin group and 7% (48 patients) in the vancomycin group.
The mean pharmacokinetic parameters of telavancin (10 mg/kg) after a single and multiple 60-minute intravenous infusions (10 mg/kg every 24 hours) are summarized in the following table.
Pharmacokinetic Parameters of Telavancin in Healthy Adults, 10 mg/kg:
| Single Dose (n=42) | Multiple Dose (n=36) | |
|---|---|---|
| Cmax (mcg/mL) | 93.6 ± 14.2 | 108 ± 26 |
| AUC0-∞ (mcg⋅hr/mL) | 747 ± 129 | --1 |
| AUC0-24h (mcg⋅hr/mL) | 666 ± 107 | 780 ± 125 |
| t1/2 (hr) | 8.0 ± 1.5 | 8.1 ± 1.5 |
| Cl (mL/hr/kg) | 13.9 ± 2.9 | 13.1 ± 2.0 |
| Vss (mL/kg) | 145 ± 23 | 133 ± 24 |
Cmax = maximum plasma concentration; AUC = area under concentration-time course; t1/2 = terminal elimination half-life; Cl = clearance; Vss = apparent volume of distribution at steady state; --1 Data not available
In healthy young adults, the pharmacokinetics of telavancin administered intravenously were linear following single doses from 5 to 12.5 mg/kg and multiple doses from 7.5 to 15 mg/kg administered once daily for up to 7 days. Steadystate concentrations were achieved by the third daily dose.
Telavancin binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The mean binding is approximately 90% and is not affected by renal or hepatic impairment.
Concentrations of telavancin in pulmonary epithelial lining fluid (ELF) and alveolar macrophages (AM) were measured through collection of bronchoalveolar lavage fluid at various times following administration of telavancin 10 mg/kg once daily for 3 days to healthy adults. Telavancin concentrations in ELF and AM exceeded the MIC90 for S. aureus (0.5 mcg/mL) for at least 24 hours following dosing.
Concentrations of telavancin in skin blister fluid were 40% of those in plasma (AUC0-24hr ratio) after 3 daily doses of 7.5 mg/kg telavancin in healthy young adults.
No metabolites of telavancin were detected in in vitro studies using human liver microsomes, liver slices, hepatocytes, and kidney S9 fraction. None of the following recombinant CYP 450 isoforms were shown to metabolize telavancin in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, 3A4, 3A5, 4A11. The clearance of telavancin is not expected to be altered by inhibitors of any of these enzymes.
In a mass balance study in male subjects using radiolabeled telavancin, 3 hydroxylated metabolites were identified with the predominant metabolite (THRX-651540) accounting for <10% of the radioactivity in urine and <2% of the radioactivity in plasma. The metabolic pathway for telavancin has not been identified.
Telavancin is primarily eliminated by the kidney. In a mass balance study, approximately 76% of the administered dose was recovered from urine and <1% of the dose was recovered from feces (collected up to 216 hours) based on total radioactivity.
The impact of age on the pharmacokinetics of telavancin was evaluated in healthy young (range 21-42 years) and elderly (range 65-83 years) subjects. The mean CrCl of elderly subjects was 66 mL/min. Age alone did not have a clinically meaningful impact on the pharmacokinetics of telavancin.
The pharmacokinetics of telavancin in patients less than 18 years of age have not been studied.
The impact of gender on the pharmacokinetics of telavancin was evaluated in healthy male (n=8) and female (n=8) subjects. The pharmacokinetics of telavancin were similar in males and females. No dosage adjustment is recommended based on gender.
The pharmacokinetics of telavancin were evaluated in subjects with normal renal function and subjects with varying degrees of renal impairment following administration of a single dose of telavancin 7.5 mg/kg (n=28). The mean AUC0-∞ values were approximately 13%, 29%, and 118% higher for subjects with CrCl >50 to 80 mL/min, CrCl 30 to 50 mL/min, and CrCl <30 mL/min, respectively, compared with subjects with normal renal function. Dosage adjustment is required in patients with CrCl ≤50 mL/min.
Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:
CrCl = [140 – age (years)] x ideal body weight (kg)* / [72 x serum creatinine (mg/dL)] {x 0.85 for female patients}
* Use actual body weight if < ideal body weight (IBW)
IBW (male) = 50 kg + 0.9 kg/cm over 152 cm height
IBW (female) = 45.5 kg + 0.9 kg/cm over 152 cm height
Following administration of a single dose of telavancin 7.5 mg/kg to subjects with end-stage renal disease, approximately 5.9% of the administered dose of telavancin was recovered in the dialysate following 4 hours of hemodialysis. The effects of peritoneal dialysis have not been studied.
Following a single intravenous dose of telavancin 7.5 mg/kg, the clearance of hydroxypropyl-beta-cyclodextrin was reduced in subjects with renal impairment, resulting in a higher exposure to hydroxypropyl-beta-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, the mean clearance values were 38%, 59%, and 82% lower, respectively, compared with subjects with normal renal function. Multiple infusions of telavancin may result in accumulation of hydroxypropyl-beta-cyclodextrin.
The pharmacokinetics of telavancin were not altered in subjects with moderate hepatic impairment (n= 8, Child-Pugh B) compared with healthy subjects with normal hepatic function matched for gender, age, and weight. The pharmacokinetics of telavancin have not been evaluated in patients with severe hepatic impairment (Child-Pugh C).
The inhibitory activity of telavancin against the following CYP 450 enzymes was evaluated in human liver microsomes: CYP 1A2, 2C9, 2C19, 2D6, and 3A4/5. Telavancin inhibited CYP 3A4/5 at potentially clinically relevant concentrations. Upon further evaluation in a Phase 1 clinical trial, telavancin was found not to inhibit the metabolism of midazolam, a sensitive CYP3A substrate (see below).
The impact of telavancin on the pharmacokinetics of midazolam (CYP 3A4/5 substrate) was evaluated in 16 healthy adult subjects following administration of a single dose of telavancin 10 mg/kg, intravenous midazolam 1 mg, and both. The results showed that telavancin had no impact on the pharmacokinetics of midazolam and midazolam had no effect on the pharmacokinetics of telavancin.
The impact of telavancin on the pharmacokinetics of aztreonam was evaluated in 11 healthy adult subjects following administration of a single dose of telavancin 10 mg/kg, aztreonam 2 g, and both. Telavancin had no impact on the pharmacokinetics of aztreonam and aztreonam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or aztreonam is recommended when both drugs are coadministered.
The impact of telavancin on the pharmacokinetics of piperacillin-tazobactam was evaluated in 12 healthy adult subjects following administration of a single dose of telavancin 10 mg/kg, piperacillin-tazobactam 4.5 g, and both. Telavancin had no impact on the pharmacokinetics of piperacillin-tazobactam and piperacillin-tazobactam had no effect on the pharmacokinetics of telavancin. No dosage adjustment of telavancin or piperacillin-tazobactam is recommended when both drugs are coadministered.
Two-week administration of telavancin in rats produced minimal renal tubular vacuolization with no changes in BUN or creatinine. These effects were not seen in studies conducted in dogs for similar duration. Four weeks of treatment resulted in reversible elevations in BUN and/or creatinine in association with renal tubular degeneration that further progressed following 13 weeks of treatment.
These effects occurred at exposures (based on AUCs) that were similar to those measured in clinical trials.
The potential effects of continuous venovenous hemofiltration (CVVH) on the clearance of telavancin were examined in an in vitro model using bovine blood. Telavancin was cleared by CVVH and the clearance of telavancin increased with increasing ultrafiltration rate.
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