CLINICAL PHARMACOLOGY
Mechanism Of Action
Oritavancin is an antibacterial drug [see CLINICAL PHARMACOLOGY].
Pharmacodynamics
The antimicrobial activity of oritavancin appears to correlate with the ratio of area under the
concentration-time curve to minimal inhibitory concentration (AUC/MIC) based on animal models of
infection.
Exposure-response analyses from both preclinical and clinical studies support the treatment of
clinically relevant Gram-positive microorganisms (e.g. S. aureus and S. pyogenes) causative of ABSSSI
with a single 1200 mg dose of ORBACTIV.
Cardiac Electrophysiology
In a thorough QTc study of 135 healthy subjects at a dose 1.3 times the 1200 mg recommended dose,
ORBACTIV did not prolong the QTc interval to any clinically relevant extent.
Pharmacokinetics
The population PK analysis was derived using data from the two Phase 3 ABSSSI clinical trials in 297
patients. The mean pharmacokinetic parameters of oritavancin in patients following a single 1200 mg
dose are presented in Table 3.
Table 3: Mean PK parameters for patients receiving a single 1200 mg dose
for ABSSSI (n=297)
Parameter |
Mean (CV%) |
Cmax (μg/mL) |
138 (23.0%) |
AUC0-24 (μg•h/mL) |
1110 (33.9%) |
AUC0-∞ (μg•h/mL) |
2800 (28.6%) |
T½,α (h) |
2.29 (49.8%) |
T½,β (h) |
13.4 (10.5%) |
T½,γ (h) |
245 (14.9%) |
Cmax, Maximum plasma concentration; AUC0-24, Area under the plasma
concentration-time curve from time zero to 24 hours, AUC0-∞ = Area under the
plasma concentration time curve from time zero to infinity; T½,α , Half-life for the
alpha phase, T½,β , Half-life for the beta phase; T½,γ , Half-life for the gamma
phase; CV% = Percent Coefficient of variation. |
Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg. The mean, population-predicted
oritavancin concentration-time profile displays a multi-exponential decline with a long terminal plasma
half-life as shown in Figure 1.
Figure 1: Population Mean Plasma Concentration-Time Profile after a Single 1200 mg dose of
Oritavancin Administered Intravenously Over 3 Hours – Semi-Log Scale
Distribution
Oritavancin is approximately 85% bound to human plasma proteins.
Based on population PK analysis, the population mean total volume of distribution is estimated to be
approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.
Exposures of oritavancin in skin blister fluid were approximately 20% of those in plasma (AUC )
after single 800 mg dose in healthy subjects.
Metabolism/Excretion
Non-clinical studies including in vitro human liver microsome studies indicated that oritavancin is not
metabolized. No mass balance study has been conducted in humans. In humans, oritavancin is slowly
excreted unchanged in feces and urine with less than 1% and 5% of the dose recovered in feces and
urine, respectively, after 2 weeks of collection.
Oritavancin has a terminal half-life of approximately 245 hours and a clearance of 0.445 L/h based on
population pharmacokinetic analyses.
Specific Populations
No dosage adjustments of ORBACTIV are required for patients with mild to severe renal or mild to
moderate hepatic impairment or other subpopulations including age, gender, race and weight.
Renal Impairment
The pharmacokinetics of oritavancin was examined in the Phase 3 ABSSSI trials in patients with normal
renal function, CrCL ≥80 mL/min (n=238), mild renal impairment, CrCL 50-79 mL/min (n=48), and
moderate renal impairment, CrCL 30-49 mL/min (n=11). Population pharmacokinetic analysis indicated
that mild to moderate renal impairment had no clinically relevant effect on the exposure of oritavancin.
No dedicated studies in dialysis patients have been conducted.
Dosage adjustment of ORBACTIV is not needed in patients with mild or moderate renal impairment. The
pharmacokinetics of oritavancin in patients with severe renal impairment have not been evaluated.
Hepatic Impairment
The pharmacokinetics of oritavancin were evaluated in study of subjects with moderate hepatic
impairment (Child-Pugh Class B) (n=20) and compared with healthy subjects (n=20) matched for gender,
age and weight. There were no relevant changes in pharmacokinetics of oritavancin in subjects with
moderate hepatic impairment.
Dosage adjustment of ORBACTIV is not needed in patients with mild or moderate hepatic impairment.
The pharmacokinetics of oritavancin in patients with severe hepatic insufficiency has not been studied.
Pediatric
The pharmacokinetics of ORBACTIV in pediatric populations (<18 years of age) has not been studied
[see Use In Specific Populations].
Age, Gender, Weight And Race
Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that gender,
age, weight or race had no clinically relevant effect on the exposure of ORBACTIV. No dosage
adjustment is warranted in these subpopulations.
Drug Interactions
In vitro studies with human liver microsomes showed that oritavancin inhibited the activities of
cytochrome P450 (CYP) enzymes 1A2, 2B6, 2D6, 2C9, 2C19, and 3A4. The observed inhibition of
multiple CYP isoforms by oritavancin in vitro is likely to be reversible and the mechanism of inhibition,
noncompetitive. In vitro studies indicate that oritavancin is neither a substrate nor an inhibitor of the
efflux transporter P-glycoprotein (P-gp).
Drugs That Inhibit Or Induce CYP450 Enzymes
A screening drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the
concomitant administration of a single 1200 mg dose of ORBACTIV with probe substrates for several
CYP450 enzymes. The results showed that ORBACTIV is a weak inducer of CYP3A4 (a decrease of
18% in the mean AUC of midazolam) and CYP2D6 (decrease of 31% in the ratio of dextromethorphan to
dextrorphan concentrations in the urine after administration of dextromethorphan). ORBACTIV was also
a weak inhibitor of CYP2C19 (increase of 15% in the ratio of omeprazole to 5-OH-omeprazole
concentrations in the plasma after administration of omeprazole) and also showed to be a weak inhibitor
of CYP2C9 (with an increase of 31% in the mean AUC of warfarin) [see WARNINGS AND PRECAUTIONS,
and DRUG INTERACTIONS].
In the screening drug-drug interaction study, co-administration of ORBACTIV resulted in an increase
of 18% in the ratio of 1-methylxanthine + 1 methylurate + 5-acetylamino-6-formylamino-3-methyluracil
(1X + 1U + AFMU) to 1,7-dimethylurate (17U) concentrations in the urine after administration of
caffeine (CYP1A2 probe substrate), and an increase of 16% in the ratio of AFMU to (1X +1U)
concentrations in the urine after administration of caffeine (N-Acetyltransferase- 2 probe substrate). Coadministration
of ORBACTIV did not change the mean systemic exposure of caffeine metabolite
(Xanthine oxidase probe substrate).
A study to assess the drug-drug interaction potential of a single 1200 mg dose of ORBACTIV on the
pharmacokinetics of S-warfarin following a single dose was conducted in 36 healthy subjects. Swarfarin
pharmacokinetics were evaluated following a single dose of warfarin 25 mg given alone, or
administered at the start, 24, or 72 hours after a single 1200 mg ORBACTIV dose. The results showed
no effect of ORBACTIV on S-warfarin C or AUC.
Microbiology
ORBACTIV is a semi-synthetic, lipoglycopeptide antibacterial drug. ORBACTIV exerts a
concentration-dependent bactericidal activity in vitro against S. aureus, S. pyogenes, and E. faecalis.
Mechanism Of Action
Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step
of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of
the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging
segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization,
permeabilization, and cell death. These multiple mechanisms contribute to the concentration-dependent
bactericidal activity of oritavancin.
Resistance
In serial passage studies, resistance to oritavancin was observed in isolates of S. aureus and E. faecalis.
Resistance to oritavancin was not observed in clinical studies.
Interaction With Other Antimicrobial Agents
In in vitro studies, oritavancin exhibits synergistic bactericidal activity in combination with gentamicin,
moxifloxacin or rifampicin against isolates of methicillin-susceptible S. aureus (MSSA), with
gentamicin or linezolid against isolates of heterogeneous vancomycin-intermediate S. aureus (hVISA),
VISA, and vancomycin-resistant S. aureus (VRSA), and with rifampin against isolates of VRSA. In vitro
studies demonstrated no antagonism between oritavancin and gentamicin, moxifloxacin, linezolid or
rifampin.
Antibacterial Activity
Oritavancin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE].
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus dysgalactiae
Streptococcus pyogenes
Enterococcus faecalis (vancomycin-susceptible isolates only)
The following in vitro data are available but their clinical significance is unknown. At least 90 percent
of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal
to the susceptible breakpoint for oritavancin against isolates of a similar organism group. However, the
efficacy of oritavancin in treating clinical infections due to these bacteria has not been established in
adequate and well-controlled clinical trials.
Gram-Positive Bacteria
Enterococcus faecium (vancomycin-susceptible isolates only)
Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro
susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the
physician as periodic reports that describe the susceptibility profile of nosocomial and communityacquired
pathogens. These reports should aid the physician in selecting an antimicrobial drug for
treatment.
Dilution Technique
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs).
These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs
should be determined using a standardized test method1,2 (broth and/or agar). Oritavancin powder is
dissolved and diluted in the presence of 0.002% polysorbate 80 and broth test medium is supplemented
with polysorbate 80 to a final concentration of 0.002%. The MIC values should be interpreted
according to the criteria provided in the Table 4.
Table 4: Susceptibility Interpretive Criteria for ORBACTIVa
Microorganism |
Minimum Inhibitory Concentration
(MIC, mcg/mL) |
S |
Ib |
Rc |
Staphylococcus aureus (including methicillinresistant
isolates) |
≤0.12 |
- |
- |
Streptococcus pyogenes, Streptococcus agalactiae,
Streptococcus dysgalactiae, Streptococcus
anginosus, Streptococcus constellatus, and
Streptococcus intermedius. |
≤0.25 |
- |
- |
Enterococcus faecalis (vancomycin-susceptible
isolates only) |
≤0.12 |
- |
- |
Abbreviations: MIC, minimum inhibitory concentration; S, Susceptible; I, intermediate; R, Resistant
aAs determined by broth microdilution with 0.002% polysorbate-80 during oritavancin dissolution and
dilution and in the final assay.
bThe current absence of resistant isolates precludes defining any results other than "Susceptible".
Isolates yielding test results other than "Susceptible" should be retested, and if the result is confirmed,
the isolate should be submitted to a reference laboratory for further testing. |
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the
pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure
the accuracy of supplies and reagents used in the assay, and the techniques of the individuals
performing the test1,2. Standard oritavancin powder should provide the following range of MIC values
noted in Table 5.
Table 5: Acceptable Quality Control Ranges for Oritavancin Susceptibility Testinga
Quality Control Organism |
Minimum Inhibitory Concentration Range
(MIC in mcg/mL) |
Staphylococcus aureus ATCC 29213 |
0.015 – 0.12 |
Streptococcus pneumoniae ATCC 49619 |
0.001 – 0.004 |
Enterococcus faecalis ATCC 29212 |
0.008 – 0.03 |
ATCC = American Type Culture Collection.
aAs determined by broth microdilution with 0.002% polysorbate-80 during oritavancin dissolution and
dilution and in the final assay1,2. |
Clinical Studies
Acute Bacterial Skin And Skin Structure Infections (ABSSSI)
A total of 1987 adults with clinically documented ABSSSI suspected or proven to be due to Grampositive
pathogens were randomized into two identically designed, randomized, double-blind, multicenter,
multinational, non-inferiority trials (Trial 1 and Trial 2) comparing a single 1200 mg intravenous
dose of ORBACTIV to intravenous vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days. The
primary analysis population (modified intent to treat, mITT) included all randomized patients who
received any study drug. Patients could receive concomitant aztreonam or metronidazole for suspected
Gram-negative and anaerobic infection, respectively. Patient demographic and baseline characteristics
were balanced between treatment groups. Approximately 64% of patients were Caucasian and 65%
were males. The mean age was 45 years and the mean body mass index was 27 kg/m2. Across both trials,
approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. A
history of diabetes was present in 14% of patients. The types of ABSSSI across both trials included
cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median
infection area at baseline across both trials was 266.6 cm2.
The primary endpoint in both trials was early clinical response (responder), defined as cessation of
spread or reduction in size of baseline lesion, absence of fever, and no rescue antibacterial drug at 48
to 72 hours after initiation of therapy.
Table 6 provides the efficacy results for the primary endpoint in Trial 1 and Trial 2 in the primary
analysis population.
Table 6: Clinical Response Rates in ABSSSI Trials using Responders1,2 at 48-72 Hours after Initiation of
Therapy
|
ORBACTIV
n /N (%) |
Vancomycin
n /N (%) |
Difference (95% CI)3 |
Trial 1 |
391/475 (82.3) |
378/479 (78.9) |
3.4 (-1.6, 8.4) |
Trial 2 |
403/503 (80.1) |
416/502 (82.9) |
-2.7 (-7.5, 2.0) |
1Cessation of spread or reduction in size of baseline lesion, absence of fever (<37.7°C) and no rescue
antibacterial drug at 48 to 72 hours.
2Patients who died at 48 to 72 hours, after initiation of therapy or who had increase in lesion size at 48 to 72
hours, after initiation of therapy or who used non-study antibacterial therapy during first 72 hours or who had an
additional, unplanned, surgical procedure or who had missing measurements during the first 72 hours from
initiation of study drug were classified as non-responders.
395% CI based on the Normal approximation to Binomial distribution. |
A key secondary endpoint in these two ABSSSI trials evaluated the percentage of 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 the two ABSSSI trials.
Table 7: Clinical Response Rates1 in ABSSSI Trials using Reduction in Lesion Area of 20% or
Greater at 48-72 Hours after Initiation of Therapy
|
ORBACTIV
n /N (%) |
Vancomycin
n /N (%) |
Difference (95% CI)2 |
Trial 1 |
413/475 (86.9) |
397/479 (82.9) |
4.1 (-0.5, 8.6) |
Trial 2 |
432/503 (85.9) |
428/502 (85.3) |
0.6 (-3.7, 5.0) |
1Patients who died at 48 to 72 hours, after initiation of therapy or who had increase in lesion size at 48 to 72 hours, after initiation of therapy or who used non-study antibacterial therapy during first 72 hours or who
had an additional, unplanned, surgical procedure or who had missing measurements during the first 72 hours
from initiation of study drug were classified as non-responders.
295% CI based on the Normal approximation to Binomial distribution. |
Another secondary efficacy endpoint in the two trials was investigator-assessed clinical success at post
therapy evaluation at Day 14 to 24 (7 to 14 days from end of blinded therapy). A patient was categorized
as a clinical success if the patient experienced a complete or nearly complete resolution of baseline
signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage,
fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with
antibacterial drugs was needed.
Table 8 summarizes the findings for this endpoint in the mITT 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 post therapy visits. Therefore,
comparisons of ORBACTIV to vancomycin based on clinical success rates at these visits cannot be
utilized to establish non-inferiority conclusions.
Table 8: Clinical Success Rates1 in ABSSSI Trials at the Follow-Up Visit (7-14 days after
end of therapy)
|
ORBACTIV
n /N (%) |
Vancomycin
n /N (%) |
Difference (95% CI)2 |
Trial 1
|
|
|
|
mITT |
378/475 (79.6) |
383/479 (80.0) |
-0.4 (-5.5, 4.7) |
CE |
362/394 (91.9) |
370/397 (93.2) |
-1.3 (-5.0,2.3) |
Trial 2 |
|
|
|
mITT |
416/503 (82.7) |
404/502 (80.5) |
2.2 (-2.6, 7.0) |
CE |
398/427 (93.2) |
387/408 (94.9) |
-1.6 (-4.9,1.6) |
1Clinical success was defined if the patient experienced a complete or nearly complete
resolution of baseline signs and symptoms as described above.
295% CI based on the Normal approximation to Binomial distribution.
3mITT population consisted of all randomized patients who received study drug; CE population
consisted of all mITT patients who did not have violations of inclusion and exclusion criteria,
completed treatment and had investigator assessment at the Follow-Up Visit. |
Outcomes By Baseline Pathogen
Table 9 shows outcomes in patients with an identified baseline
pathogen in the microbiological Intent-to-Treat (microITT) population in a pooled analysis of Trial 1
and Trial 2. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical
success rates at follow-up study day 14 to 24.
Table 9: Outcomes by Baseline Pathogen (microITT)
|
At 48-72 hours |
Study day 14 to 24 |
Early Clinical Responder1 |
≥ 20% reduction in lesion size2 |
Clinical Success3 |
Pathogen4 |
ORBACTIV
n/N (%) |
Vancomycin
n/N (%) |
ORBACTIV
n/N (%) |
Vancomycin
n/N (%) |
ORBACTIV
n/N (%) |
Vancomycin
n/N (%) |
Staphylococcus
aureus |
388/472 (82.2) |
395/473 (83.5) |
421/472 (89.2) |
407/473 (86.0) |
390/472 (82.6) |
398/473 (84.1) |
Methicillinsusceptible |
222/268 (82.8) |
233/272 (85.7) |
231/268 (86.2) |
232/272 (85.3) |
220/268 (82.1) |
229/272 (84.2) |
Methicillinresistant |
166/204 (81.4) |
162/201 (80.6) |
190/204 (93.1) |
175/201 (87.1) |
170/204 (83.3) |
169/201 (84.1) |
Streptococcus
pyogenes |
21/31 (67.7) |
23/32 (71.9) |
24/31 (77.4) |
24/32 (75.0) |
25/31 (80.6) |
23/32 (71.9) |
Streptococcus
agalactiae |
7/8 (87.5) |
12/12 (100.0) |
8/8 (100.0) |
12/12 (100.0) |
7/8 (87.5) |
11/12 (91.7) |
Streptococcus
dysgalactiae |
7/9 (77.8) |
6/6 (100.0) |
6/9 (66.7) |
5/6 (83.3) |
7/9 (77.8) |
3/6 (50.0) |
Streptococcus
anginosus group |
28/33 (84.8) |
40/45 (88.9) |
29/33 (87.9) |
42/45 (93.3) |
25/33 (75.8) |
38/45 (84.4) |
Enterococcus
faecalis |
11/13 (84.6) |
10/12( 83.3) |
10/13 (76.9) |
8/12 (66.7) |
8/13 (61.5) |
9/12 (75.0) |
1Early clinical response defined as a composite of the cessation of spread or reduction in size of baseline lesion, absence of fever
and no rescue antibacterial drug at 48-72 hours.
2Patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy.
3Clinical success was defined if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms as
described above.
4Baseline bacteremia in the oritavancin arm with relevant microorganisms causing ABSSSI included four subjects with MSSA and
seven subjects with MRSA. Eight of these eleven subjects were responders at 48 to 72 hours after initiation of therapy. |
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility
Tests for Bacteria that Grow Aerobically; Approved Standard – Tenth Edition. CLSI document M7-
A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA
19087, 2015.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26, Clinical and
Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, 2016.