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Dalvance

CLINICAL PHARMACOLOGY

Mechanism Of Action

Dalbavancin is an antibacterial drug.

Pharmacodynamics

The antibacterial activity of dalbavancin appears to best correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) for Staphylococcus aureus based on animal models of infection. An exposure-response analysis of a single study in patients with complicated skin and skin structure infections supports the two-dose regimen [see DOSAGE AND ADMINISTRATION].

Cardiac Electrophysiology

In a randomized, positive- and placebo-controlled, thorough QT/QTc study, 200 healthy subjects received dalbavancin 1000 mg IV, dalbavancin 1500 mg IV, oral moxifloxacin 400 mg, or placebo. Neither dalbavancin 1000 mg nor dalbavancin 1500 mg (supratherapeutic dose) had any clinically relevant adverse effect on cardiac repolarization.

Pharmacokinetics

Dalbavancin pharmacokinetic parameters have been characterized in healthy subjects, patients, and specific populations. Pharmacokinetic parameters following administration of a single intravenous 1000 mg dose were as shown in Table 3. The pharmacokinetics of dalbavancin can be described using a three-compartment model.

Table 3: Dalbavancin Pharmacokinetic Parameters in Healthy Subjects

Parameter Single 1000 mg Dose
Cmax (mg/L) 287 (13.9)1
AUC0-24 (mg•h/L) 3185 (12.8)1
AUC0-Day7(mg•h/L) 11160 (41.1)2
AUC0-inf(mg•h/L) 23443 (40.9)2
Terminal t½(h) 346 (16.5)2,3
CL (L/h) 0.0513 (46.8)2
All values are presented as mean (% coefficient of variation)
1Data from 50 healthy subjects.
2Data from 12 healthy subjects.
3Based upon population pharmacokinetic analyses of data from patients, the effective half-life is approximately 8.5 days (204 hours).

In healthy subjects, dalbavancin AUC0-24h and Cmax both increased proportionally to dose following single IV dalbavancin doses ranging from 140 mg to 1500 mg, indicating linear pharmacokinetics.

The mean plasma concentration-time profile for dalbavancin at the recommended two-dose regimen of 1000 mg followed one week later by 500 mg is shown in Figure 2.

Figure 2: Mean (± standard deviation) dalbavancin plasma concentrations versus time in healthy subjects (n=10) following IV administration over 30 minutes of 1000 mg dalbavancin (Day 1) and 500 mg dalbavancin (Day 8).

Dalbavancin plasma concentrations versus time in healthy subjects - Illustration

No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to eight weeks, with 1000 mg on Day 1 followed by up to seven weekly 500 mg doses, in healthy adults with normal renal function.

Distribution

Dalbavancin is reversibly bound to human plasma proteins, primarily to albumin. The plasma protein binding of dalbavancin is approximately 93% and is not altered as a function of drug concentration, renal impairment, or hepatic impairment. The mean concentrations of dalbavancin achieved in skin blister fluid remain above 30 mg/L up to 7 days (approximately 146 hours) post dose, following 1000 mg IV dalbavancin. The mean ratio of the AUC0-144 hrs in skin blister fluid/AUC0-144 hrs in plasma is 0.60 (range 0.44 to 0.64).

Metabolism

In vitro studies using human microsomal enzymes and hepatocytes indicate that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. A minor metabolite of dalbavancin (hydroxy-dalbavancin) has been observed in the urine of healthy subjects. Quantifiable concentrations of the hydroxy-dalbavancin metabolite have not been observed in human plasma (lower limit of quantitation = 0.4 μg/mL) [see DRUG INTERACTIONS].

Excretion

Following administration of a single 1000 mg dose in healthy subjects, 20% of the dose was excreted in feces through 70 days post dose. An average of 33% of the administered dalbavancin dose was excreted in urine as unchanged dalbavancin and approximately 12% of the administered dose was excreted in urine as the metabolite hydroxy-dalbavancin through 42 days post dose.

Specific Populations

Renal Impairment: The pharmacokinetics of dalbavancin were evaluated in 28 subjects with varying degrees of renal impairment and in 15 matched control subjects with normal renal function. Following a single dose of 500 mg or 1000 mg dalbavancin, the mean plasma clearance (CLT) was reduced 11%, 35%, and 47% in subjects with mild (CLCR 50 to 79 mL/min), moderate (CLCR 30 to 49 mL/min), and severe (CLCR less than 30 mL/min), renal impairment, respectively, compared to subjects with normal renal function. The clinical significance of the decrease in mean plasma CLT, and the associated increase in AUC0-∞ noted in these pharmacokinetic studies of dalbavancin in subjects with severe renal impairment has not been established [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

No dosage adjustment is necessary for patients with CLCR greater than 30 mL/min or patients receiving hemodialysis. The recommended two-dose regimen for dalbavancin in patients with severe renal impairment who are not receiving regularly scheduled hemodialysis is 750 mg followed one week later by 375 mg.

Dalbavancin pharmacokinetic parameters in subjects with end-stage renal disease receiving regularly scheduled hemodialysis (three times/week) are similar to those observed in subjects with mild to moderate renal impairment, and less than 6% of an administered dose is removed after three hours of hemodialysis. Therefore, no dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and dalbavancin may be administered without regard to the timing of hemodialysis in such patients [see DOSAGE AND ADMINISTRATION and OVERDOSAGE].

Hepatic Impairment: The pharmacokinetics of dalbavancin were evaluated in 17 subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B or C) and compared to those in nine matched healthy subjects with normal hepatic function. The mean AUC0-336 hrs was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however, the mean AUC0-336 hrs decreased 28% and 31% in subjects with moderate and severe hepatic impairment respectively, compared to subjects with normal hepatic function. The clinical significance of the decreased AUC0-336 hrs in subjects with moderate and severe hepatic function is unknown.

No dosage adjustment is recommended for patients with mild hepatic impairment. Caution should be exercised when prescribing dalbavancin to patients with moderate or severe hepatic impairment as no data are available to determine the appropriate dosing.

Gender: Clinically significant gender-related differences in dalbavancin pharmacokinetics have not been observed either in healthy subjects or in patients with infections. No dosage adjustment is recommended based on gender.

Geriatric Patients: Clinically significant age-related differences in dalbavancin pharmacokinetics have not been observed in patients with infections. No dosage adjustment is recommended based solely on age.

Pediatric Patients: The pharmacokinetics of dalbavancin in pediatric populations < 12 years of age have not been established.

Drug Interactions

Nonclinical studies demonstrated that dalbavancin is not a substrate, inhibitor, or inducer of CYP450 isoenzymes. In a population pharmacokinetic analysis, dalbavancin pharmacokinetics were not affected by co-administration with known CYP450 substrates, inducers or inhibitors, nor by individual medications including acetaminophen, aztreonam, fentanyl, metronidazole, furosemide, proton pump inhibitors (omeprazole, esomeprazole, pantoprazole, lansoprazole), midazolam, and simvastatin.

Microbiology

Mechanism of Action

Dalbavancin, a semisynthetic lipoglycopeptide, interferes with cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thus preventing cross-linking. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans treated according to the recommended dosage regimen.

Mechanism of Resistance

The development of bacterial isolates resistant to dalbavancin has not been observed, either in vitro, in studies using serial passage, or in animal infection experiments.

Interaction with Other Antimicrobials

When tested in vitro, dalbavancin demonstrated synergistic interactions with oxacillin and did not demonstrate antagonistic or synergistic interactions with any of the following antibacterial agents of various classes: gentamicin, vancomycin, levofloxacin, clindamycin, quinupristin/dalfopristin, linezolid, aztreonam, rifampin or daptomycin. The clinical significance of these in vitro findings is unknown.

Dalbavancin has been shown to be active against the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE].

Gram-positive bacteria

Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus pyogenes

Streptococcus agalactiae

Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus)

The following in vitro data are available, but their clinical significance is unknown. In addition, at least 90% of organisms in the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the dalbavancin susceptible breakpoint of 0.12 mcg/mL. However, the safety and efficacy of dalbavancin in treating clinical infections due to these bacteria have not been established in adequate well-controlled clinical trials.

Gram-positive bacteria

Enterococcus faecium (vancomycin-susceptible isolates only)
Enterococcus faecalis (vancomycin-susceptible isolates only)

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1,2 When determining dalbavancin MICs, polysorbate-80 (P-80), should be added at a final concentration of 0.002% to freshly prepared or frozen microtiter trays. The MIC values should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques

Dalbavancin disks for diffusion susceptibility testing are not available. Disk diffusion is not a reliable method for determining the in vitro activity of dalbavancin.

Table 4: Susceptibility Test Interpretive Criteria for Dalbavancin

Pathogen MIC (mcg/mL)a Zone Diameter (mm)
S I R S I R
Staphylococcus aureus (including methicillin-resistant isolates) ≤ 0.12 - - - - -
Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group ≤ 0.12 - - - - -
aThe current absence of data on resistant isolates precludes defining any category other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.

A report of “Susceptible” indicates that the antibacterial agent is likely to inhibit growth of the pathogen if the antibacterial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2 Standard dalbavancin powder should provide the following range of MIC values noted in Table 5.

Table 5: Acceptable MIC Quality Control Ranges for Dalbavancin

Quality Control Strain MIC Range (μg/mL)
Staphylococcus aureus ATCC ®29213 0.03-0.12
Streptococcus pneumoniae ATCC ®49619a 0.008-0.03
Enterococcus faecalis ATCC ®29212 0.03-0.12
ATCC® = American Type Culture Collection
aThis organism may be used for validation of susceptibility test results when testing Streptococcus species other than S. pneumoniae.

Animal Toxicology And/Or Pharmacology

Increases in serum levels of liver enzymes (ALT, AST), associated with microscopic findings in the liver were noted in toxicology studies in rats and dogs where dalbavancin was administered daily for 28 to 90 days. Hepatocellular necrosis was observed in dogs dosed at ≥ 10 mg/kg/day for longer than 2 months, i.e., at approximately 5 to 7 times the expected human dose on an exposure basis. Histiocytic vacuolation and hepatocyte necrosis were observed in rats dosed daily at 40 and 80 mg/kg/day, respectively, for 4 weeks, (approximately 3 and 6 times the expected human dose on an exposure basis, respectively). In addition, renal toxicity characterized by increases in serum BUN and creatinine and microscopic kidney findings was observed in rats and dogs at doses 5 to 7 times the expected human dose on an exposure basis.

The relationship between these findings in the animal toxicology studies after 28 and 90 consecutive days of dosing to the indicated clinical dosing of 2 doses 7 days apart are unclear.

Clinical Studies

Acute Bacterial Skin and Skin Structure Infections

Adult patients with ABSSSI were enrolled in two Phase 3, randomized, double-blind, double-dummy clinical trials of similar design (Trial 1 and Trial 2). The Intent-to-Treat (ITT) population included 1,312 randomized patients. Patients were treated for two weeks with either a two-dose regimen of intravenous DALVANCE (1000 mg followed one week later by 500 mg) or intravenous vancomycin (1000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). DALVANCE-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens.

The specific infections in these trials included cellulitis (approximately 50% of patients across treatment groups), major abscess (approximately 30%), and wound infection (approximately 20%). The median lesion area at baseline was 341 cm² . In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline, defined as temperature 38°C or higher (approximately 85% of patients), white blood cell count greater than 12,000 cells/mm³(approximately 40%), or 10% or more band forms on white blood cell differential (approximately 23%). Across both trials, 59% of patients were from Eastern Europe and 36% of patients were from North America. Approximately 89% of patients were Caucasian and 58% were males. The mean age was 50 years and the mean body mass index was 29.1 kg/m² .

The primary endpoint of these two ABSSSI trials was the clinical response rate where responders were defined as patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6° C upon repeated measurement. Table 6 summarizes overall clinical response rates in these two ABSSSI trials using the pre-specified primary efficacy endpoint in the ITT population.

Table 6: Clinical Response Rates in ABSSSI Trials at 48-72 Hours after Initiation of Therapy

  DALVANCE
n/N (%)
Vancomycin/Linezolid
n/N (%)
Difference (95% CI)3
Trial 1 240/288 (83.3%) 233/285
(81.8%)
1.5%
(-4.6, 7.9)
Trial 2 285/371 (76.8%) 288/368
(78.3%)
-1.5%
(-7.4, 4.6)
1There were 7 patients who did not receive treatment and were counted as non-responders: 6 dalbavancin patients (3 in each trial) and one vancomycin/linezolid patient in Trial 2.
2Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders.
3The 95% Confidence Interval (CI) is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

A key secondary endpoint in these two ABSSSI trials evaluated the percentage of ITT patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. Table 7 summarizes the findings for this endpoint in these two ABSSSI trials.

Table 7: Patients in ABSSSI Trials with Reduction in Lesion Area of 20% or Greater at 48-72 Hours after Initiation of Therapy

  DALVANCE
n/N (%)
Vancomycin /Linezolid
n/N (%)
Difference (95% CI)3
Trial 1 259/288
(89.9%)
259/285
(90.9%)
-1.0%
(-5.7, 4.0)
Trial 2 325/371
(87.6%)
316/368
(85.9%)
1.7%
(-3.2, 6.7)
1There were 7 patients (as described in Table 6) who did not receive treatment and were counted as non-responders.
2Patients who died or used non-study antibacterial therapy or had missing measurements were classified as non-responders.
3The 95% CI is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

Another secondary endpoint in these two ABSSSI trials was the clinical success rate assessed at a follow-up visit occurring between Days 26 to 30. Clinical Success at this visit was defined as having a decrease in lesion size (both length and width measurements), a temperature of 37.6° C or lower, and meeting pre-specified criteria for local signs: purulent discharge and drainage absent or mild and improved from baseline, heat/warmth & fluctuance absent, swelling/induration & tenderness to palpation absent or mild. Table 8 summarizes clinical success rates at a follow-up visit for the ITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the follow-up visits. Therefore, comparisons of DALVANCE to vancomycin/linezolid based on clinical success rates at these visits cannot be utilized to establish non-inferiority.

Table 8:Clinical Success Rates in ABSSSI Trials at Follow-Up (Day 26 to 30)

  DALVANCE
n/N (%)
Vancomycin/Linezolid
n/N (%)
Difference (95% CI)3
Trial 1
  ITT 241/288 (83.7%) 251/285
(88.1%)
-4.4%
(-10.1, 1.4)
  CE 212/226 (93.8%) 220/229
(96.1%)
-2.3%
(-6.6, 2.0)
Trial 2
  ITT 327/371 (88.1%) 311/368
(84.5%)
3.6%
(-1.3, 8.7)
  CE 283/294 (96.3%) 257/272
(94.5%)
1.8%
(-1.8, 5.6)
1There were 7 patients (as described in Table 6) who did not receive treatment and were counted as failures in the ITT analysis.
2Patients who died, used non-study antibacterial therapy, or had an unplanned surgical intervention 72 hours after the start of therapy were classified as Clinical Failures.
3The 95% CI is computed using the Miettinen and Nurminen approach, stratified by baseline fever status.

Table 9 shows outcomes in patients with an identified baseline pathogen, using pooled data from Trials 1 and 2 in the microbiological ITT (microITT) population. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up (Day 26 to 30), as defined above.

Table 9: Outcomes by Baseline Pathogen (MicroITT)

Pathogen Early Clinical Response at 48-72 hours
Early Responder2 ≥ 20% reduction in lesion size Clinical Success at Day 26 to 30
DALVANCE
n/N (%)
Comparator
n/N (%)
DALVANCE
n/N (%)
Comparator
n/N (%)
DALVANCE
n/N (%)
Comparator
n/N (%)
Staphylococcus aureus 206/257 (80.2) 219/256 (85.5) 239/257 (93.0) 232/256 (90.6) 217/257 (84.4) 229/256 (89.5)
  Methicillin-susceptible 134/167 (80.2) 163/189 (86.2) 156/167 (93.4) 173/189 (91.5) 142/167 (85.0) 171/189 (90.5)
  Methicillin-resistant 72/90 (80.0) 56/67 (83.6) 83/90 (92.2) 59/67 (88.1) 75/90 (83.3) 57/67 (85.1)
Streptococcus agalactiae 6/12 (50.0) 11/14 (78.6) 10/12 (83.3) 10/14 (71.4) 10/12 (83.3) 11/14 (78.6)
Streptococcus pyogenes 28/37 (75.7) 24/36 (66.7) 32/37 (86.5) 27/36 (75.0) 33/37 (89.2) 32/36 (88.9)
Streptococcus anginosus group 18/22 (81.8) 23/ 25 (92.0) 21/22 (95.5) 25/25 (100.0) 21/22 (95.5) 23/25 (92.0)
1There were 2 patients in the dalbavancin arm with methicillin-susceptible S. aureus at baseline who did not receive treatment and were counted as non-responders/failures.
2Early Responders are patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6° C upon repeated measurement.
3All patients in the clinical trials had blood cultures obtained at baseline. A total of 16 ABSSSI patients receiving dalbavancin had positive cultures at baseline for one of the above pathogens. Isolates included eleven S. aureus, three S. agalactiae, one S. pyogenes, and one S anginosus. Eleven of these patients (69%) were clinical responders at 48-72 hours and clinical successes at Day 26 to 30.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antibiotic Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Ninth Edition. CLSI document M07-A9. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement. CLSI document M100-S23 Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

Last reviewed on RxList: 6/9/2014
This monograph has been modified to include the generic and brand name in many instances.

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