Vibativ (Page 5 of 9)

11 DESCRIPTION

VIBATIV contains telavancin hydrochloride (Figure 1), a lipoglycopeptide antibacterial that is a synthetic derivative of vancomycin.

The chemical name of telavancin hydrochloride is vancomycin, N3”-[2-(decylamino)ethyl]-29-[[(phosphono-methyl)-amino]-methyl]- hydrochloride. Telavancin hydrochloride has the following chemical structure:

Figure 1: Telavancin Hydrochloride

Figure 1

Telavancin hydrochloride is an off-white to slightly colored amorphous powder with the empirical formula C80 H106 Cl2 N11 O27 P•xHCl (where x = 1 to 3) and a free-base molecular weight of 1755.6. It is highly lipophilic and slightly soluble in water.

VIBATIV is a sterile, preservative-free, white to slightly colored lyophilized powder containing telavancin hydrochloride (equivalent to either 250 mg or 750 mg of telavancin as the free base) for intravenous use. The inactive ingredients are Hydroxypropylbetadex, Ph. Eur (hydroxypropyl-beta-cyclodextrin) (2500 mg per 250 mg telavancin, 7500 mg per 750 mg telavancin), mannitol (312.5 mg per 250 mg telavancin, 937.5 mg per 750 mg telavancin), and sodium hydroxide and hydrochloric acid used in minimal quantities for pH adjustment. When reconstituted, it forms a clear to slightly colored solution with a pH of 4.5 (4.0 to 5.0).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Telavancin is an antibacterial drug [see Clinical Pharmacology (12.4) ].

12.2 Pharmacodynamics

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.

Cardiac Electrophysiology

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 VIBATIV 7.5 mg/kg, VIBATIV 15 mg/kg, positive control, or placebo infused over 60 minutes once daily for 3 days. Based on interpolation of the data from VIBATIV 7.5 mg/kg and 15 mg/kg, the mean maximum baseline-corrected, placebo-corrected QTc prolongation at the end of infusion was estimated to be 12-15 msec for VIBATIV 10 mg/kg and 22 msec for the positive control (Table 7). By 1 hour after infusion the maximum QTc prolongation was 6-9 msec for VIBATIV and 15 msec for the positive control.

Table 7: Mean and Maximum QTcF Changes from Baseline Relative to Placebo
QTcF 1 Change from Baseline

1 Fridericia corrected

2 Upper CL from a 2-sided 90% CI on difference from placebo (msec)

Mean(Upper 90% Confidence Limit 2 )msec Maximum(Upper 90% Confidence Limit)msec
VIBATIV 7.5 mg/kg 4.1 (7) 11.6 (16)
VIBATIV 15 mg/kg 4.6 (8) 15.1 (20)
Positive Control 9.5 (13) 21.6 (26)

ECGs were performed prior to and during the treatment period in patients receiving VIBATIV 10 mg/kg in 3 cSSSI studies to monitor QTc intervals. In these trials, 214 of 1029 (21%) patients allocated to treatment with VIBATIV 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 VIBATIV group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 VIBATIV 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 VIBATIV 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.

12.3 Pharmacokinetics

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 Table 8.

Table 8: Pharmacokinetic Parameters of Telavancin in Healthy Adults, 10 mg/kg

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

Single Dose Multiple Dose
(n=42) (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

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. Steady-state concentrations were achieved by the third daily dose.

Distribution

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 VIBATIV 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 VIBATIV in healthy young adults.

Metabolism

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.

Excretion

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.

Specific Populations

Geriatric Patients

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 [see Use in Specific Populations (8.5) ].

Pediatric Patients

The pharmacokinetics of telavancin in patients less than 18 years of age have not been studied.

Gender

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.

Renal Impairment

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 [see Dosage and Administration (2) ].

Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:

CrCl = [140 – age (years)] x ideal body weight (kg)* {x 0.85 for female patients}
[72 x serum creatinine (mg/dL)]

*Use actual body weight if < ideal body weight (IBW)
IBW (male) = 50 kg + 0.9 kg/cm over 152 cm heightIBW (female) = 45.5 kg + 0.9 kg/cm over 152 cm height

Following administration of a single dose of VIBATIV 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 VIBATIV 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 VIBATIV may result in accumulation of hydroxypropyl-beta-cyclodextrin.

Hepatic Impairment

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).

Drug Interactions

In Vitro

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).

Midazolam

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 VIBATIV 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.

Aztreonam

The impact of telavancin on the pharmacokinetics of aztreonam was evaluated in 11 healthy adult subjects following administration of a single dose of VIBATIV 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.

Piperacillin-tazobactam

The impact of telavancin on the pharmacokinetics of piperacillin-tazobactam was evaluated in 12 healthy adult subjects following administration of a single dose of VIBATIV 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.

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