By Emily Mui, PharmD, Stanford University
Dr. Mui reports no financial relationships in this field of study.
Dalbavancin is a lipoglycopeptide antibiotic for intravenous administration with activity against Gram-positive organisms, including methicillin resistant Staphylococcus aureus that is distinguished by its extraordinarily long serum half-life that allows once weekly dosing.
GENERIC NAME: Dalbavancin
TRADE NAME IN U.S. Dalvance™
U.S. FDA APPROVAL DATE: May 23, 2014
SIMILAR APPROVED DRUGS: Televancin, like dalbavancin, is a lipoglycopeptide. Both are related to the glycopeptide antibiotic, vancomycin.
U.S. FDA- APPROVED INDICATIONS
Treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus).< /p>
The presence of the long fatty acid chain correlates with an extended serum half-life and, by interacting with the lipid cell membrane, improves antibacterial activity. The 3-3-dimethylaminopropyl amide substituent also enhances antibacterial activity.
This lipoglycopeptide, like vancomycin, 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 S. aureus and S. pyogenes at clinically relevant concentrations. It is active in vitro against vancomycin-intermediate S. aureus (VISA), but not against vancomycin-resistant S. aureus nor against vancomycin-resistant Enterococcus faecium (VRE) caused by vanA. It does have activity against the much less common VRE carrying vanB.
The antibacterial activity of dalbavancin is concentration-dependent with AUC/MIC being the optimal correlate.
PHARMACOKINETICS
Pharmacokinetic parameters following a single 1,000mg intravenous dose of dalbavancin:
Dalbavancin AUC 0-24h and Cmax both increase proportionally to dose following single IV dalbavancin doses ranging from 140mg to 1500mg, indicating linear pharmacokinetics. No apparent accumulation of dalbavancin was observed following multiple IV infusions administered once weekly for up to 8 weeks with 1000mg on Day 1, followed by up to seven weekly 700mg doses in healthy adults with normal renal function (see table on top of next page).
Distribution: Reversibly bound to plasma protein (~93%) with a volume of distribution reported to be 9.75 – 15.7 L in adults.
Metabolism: Not a substrate, inhibitor or inducer of CYP450 isoenzyme. Minor metabolite of dalbavancin (hydroxyl-dalbavancin) has been observed in the urine of healthy subjects, but not in human plasma.
Excretion:
- 20% excreted in feces through 70 days post dose
- 33% excreted in urine as unchanged dalbavancin through 42 days post dose
- 12% excreted in urine as metabolite through 42 days post dose
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 500mg or 1000mg dalbavancin, the mean plasma clearance was reduced 11%, 35%, and 47% in subjects with mild (CrCL 50-79mL/min), moderate (30-49 mL/min), and severe (<30mL/min) renal function. No dosage adjustment necessary for patients with CrCL > 30 ML/min or patients receiving hemodialysis. The recommended 2-dose regimen for dalbavancin in patients with severe renal impairment who are not receiving regularly scheduled hemodialysis 750mg followed by one week later 375mg.
Dalbavancin PK parameters in subjects with end-stage renal disease receiving regularly scheduled hemodialysis (3x/week) are similar to those observed in subjects with mild to moderate renal impairment. Less than 6% of an administered dose is removed after three hours of hemodialysis, thus no dosage adjustment is recommended of patients receiving regularly schedule hemodialysis, and dalbavancin may be administered without regards to timing of hemodialysis.
Hepatic Impairment:
The PK of dalbavancin were evaluated in 17 subjects with mild, moderate, severe hepatic impairment (Child-Pugh class A, B or C) and compared to those with nine matched healthy subjects with normal hepatic function. The mean AUC was unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function; however the mean AUC 0-336 hours decreased 28% and 31% in subjects with moderate and severe hepatic impairment respectively, compared to those with normal hepatic function. The manufacturers do not recommend a dosage adjustment for mild hepatic impairment, but caution should be exercised when prescribing dalbavancin in patients with moderate and severe haptic function.
CLINICAL TRIALS/EVIDENCE SUMMARY
In both DISCOVER 1 and 2, patients with ABSSI were randomized to receive 2 intravenous doses of dalbavancin (1000 mg on day 1 and 500 mg on day 8) or to receive vancomycin 1000 mg or 15 mg/kg every 12 hours with an option to switch to orally administered linezolid after 3 days. The primary endpoint in each trial was the cessation of increase in size of the lesion at 48-72 hours and absence of fever. In DISCOVER 1, this endpoint was achieved in 83.3% of dalbavancin and 81.8% of vancomycin/linezolid recipient. In DISCOVER 2, the primary endpoint was achieved in 76.8% of dalbavancin and 78.3% of vancomycin/linezolid patients.
See Clinical Response Rates in ABSSSI Trials at 48-72 hours after initiation of therapy in table below.
See secondary endpoints 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 in table below.
Secondary endpoint evaluated the clinical success rate at follow-up visit occurring between day 26–30. Clinical success at this visit was defined as having a decrease in lesion size (both length and width measurement), temperature of 37.6 C or lower, meeting pre-specified criteria for local signs: purulent discharge and drainage absent or mild and improved from baseline, heat/warmth & fluctuating absent, swelling/induration & tenderness to palpitation absent or mild.
ADVERSE EFFECTS: Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with dalbavancin and 80/1224 (6.5%) of patients treated with comparator. Dalbavancin was discontinued in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients.
The following selected adverse reactions were reported in dalbavancin patients at a rate of <2% in clinical trials:
- Blood and lymphatic system disorders: anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis
- Gastrointestinal disorders: GI hemorrhage, melena, hematochezia, abdominal pain
- Infusion related reactions
- Hepatobiliary disorders: Hepatotoxicity, hepatic transaminase increase, blood alkaline phosphatase increased, INR increased.
- Among patients with normal baseline ALT levels, more dalbavancin than comparator-treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs 2 (0.2%), respectively including three subjects with post-baseline ALT values greater than 10 times ULN.
- 8/12 patients related with dalbavancin and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse.
- One dalbavancin treated patient in a phase 1 trial had post-baseline ALT elevations greater than 20 times ULN.
- ALT elevations were reversible in all subjects.
- No comparator-treated subject with normal baseline transaminase had post-baseline ALT elevations greater than 10 times ULN
- Anaphylacotid reactions
- Clostridium difficile, oral candidiasis, vulvovaginal mycotic infection
- Vascular disorders: flushing, phlebitis, wound hemorrhage, spontaneous hematoma
CONTRAINDICATIONS/WARNINGS/PRECAUTIONS:
- Contraindicated in patients with known hypersensitivity to dalbavancin. No data available on cross-reactivity between dalbavancin and other glycopeptides, including vancomycin.
- Infusion related reactions- dalbavancin must be infused over 30 minutes to minimize risk of infusion-related reactions. Rapid infusion can cause reactions that resemble "Red-Man Syndrome", including flushing of upper body, urticarial, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.
- In phase 2/3 trials, more dalbavancin treated subjects than comparator-treated subjects with normal baseline transaminase levels had post-baseline ALT elevations greater than 3 times the upper limit of normal. Overall, the abnormal LFT tests were reported with similar frequency in the dalbavancin and comparator arms.
- Use in Special populations
- Pregnancy – category C
- There is a lack of well-controlled studies with dalbavancin in pregnant women. In rat and rabbit studies, there was no evidence of embryo or fetal toxicity found at doses of 15mg/kg/day (1.2 and 0.7 times the human dose based on exposure, respectively). Delayed fetal maturation was seen in rats at doses of 45mg/kg/day (3.5 times the human dose based on exposure).
- Nursing mothers – dalbavancin is excreted in the milk of lactating rats, however it is unknown whether or not dalbavancin or its metabolite is excreted in human milk.
- Pediatric use –safety and efficacy not established
DRUG INTERACTIONS
- No clinical drug-drug interaction studies have been conducted with Dalbavancin. There is minimal potential for drug-drug interaction between dalbavancin and cytochrome P450 substrates, inhibitors, or inducers.
- No known food-drug interactions
CONCLUSIONS
Dalbavancin is a new once weekly antimicrobial FDA for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus). Dalbavancin appears to be well tolerated, although patients in clinical trials of serious skin infections have been shown to develop serum aminotransferase elevations while on therapy. The acquisition cost of Dalbavancin is considerably more expensive than other broad-spectrum gram-positive agents; however its once weekly administration may offer savings of resources in the outpatient setting.
REFERENCES
- Dalbavancin (Dalvance), 2014. Package Insert
- Zhanel GG, Calic D, Schweizer F et al. New Lipoglycopeptides A comparative review of dalbavancin, Ortivancin and Telavancin. 2010; 70 (7): 859-886
- Boucher HW, Wilcox M, Talbot GH, et al. Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection. 2014;370:2169-79.
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