ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 2005, p. 148–152
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Vol. 49, No. 1
Pharmacokinetics of Oritavancin in Plasma and Skin Blister Fluid
following Administration of a 200-Milligram Dose for 3 Days
or a Single 800-Milligram Dose
Gerald J. Fetterly,1* Christine M. Ong,2Sujata M. Bhavnani,1† Jeffrey S. Loutit,3
Steven B. Porter,3Lisa G. Morello,3Paul G. Ambrose,1† and David P. Nicolau2
Cognigen Corporation, Buffalo, New York1; Center for Anti-Infective Research and Development,
Hartford Hospital, Hartford, Connecticut2; InterMune, Inc., Brisbane, California3
Received 25 February 2004/Returned for modification 24 April 2004/Accepted 25 September 2004
Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin
structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The
disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model.
Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject
discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3
days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister
fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and
exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations
were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, phar-
macokinetic analysis was performed. Differences between treatment groups in ratios for area under the
concentration-time curve for blister fluid and plasma (AUCblister fluid/AUCplasmaratios) were evaluated using
a t test (? ? 0.05). Mean maximum concentration of drug in plasma or blister fluid was approximately 8-fold
and 11-fold higher in plasma than in blister fluid following the 200- or 800-mg doses of oritavancin, respec-
tively. Mean AUCblister fluid/AUCplasmaratios at 24 h were 0.190 (standard deviation [SD], 0.052) and 0.182 (SD,
0.062) for groups A and B, respectively (P ? 0.791). To place these results in a clinical context, mean drug
concentrations in blister fluid exceed the oritavancin MIC at which 90% of strains are inhibited of Staphylo-
coccus aureus (2 ?g/ml) by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h following adminis-
tration of both dosing regimens. These results support the potential use of oritavancin for the treatment of
Oritavancin, a semisynthetic glycopeptide, is an intravenous
antibiotic agent being developed for the treatment of gram-
positive bacterial infections. It is a chemical modification of the
naturally occurring glycopeptide LY264826 (5). The modifica-
tion, N-alkyl-linked additions on one of the two amino sugars,
confers activity against vancomycin-resistant enterococci. It
has a molecular weight of 1,989.0 and a molecular formula of
The antibacterial spectrum of oritavancin includes Staphylo-
coccus aureus, including methicillin-resistant strains; Staphylo-
coccus epidermidis and other coagulase-negative staphylococci,
including methicillin-resistant and some teicoplanin-resistant
strains; enterococci, including vancomycin-resistant, teicopla-
nin-resistant (vanA) isolates of Enterococcus faecium and En-
terococcus faecalis and the intrinsically vancomycin-resistant
species Enterococcus gallinarum and Enterococcus casseliflavus;
and streptococci, including Streptococcus pyogenes and Strepto-
coccus pneumoniae, including penicillin-resistant isolates.
Rapid bactericidal in vitro activity against most isolates of E.
faecalis and E. faecium is a property of oritavancin that distin-
guishes it from vancomycin, ampicillin, linezolid, and quinu-
A phase 1 study in healthy subjects has demonstrated the
elimination of oritavancin to be very slow, with approximately
6% of the dose eliminated from the body within a 1-week
period after single-dose intravenous infusion (1). The plasma
pharmacokinetics (PK) of oritavancin have been evaluated in
several single- and multiple-dose clinical pharmacology stud-
ies. Across studies, oritavancin displayed linear pharmacoki-
netics for weight-based doses ranging from 0.02 to 3 mg/kg of
body weight and fixed doses from 100 to 600 mg. Based on
population pharmacokinetic analyses, oritavancin plasma con-
centrations display a multiexponential decline and are well
described by a three-compartment model with corresponding
apparent tissue distribution (? and ?) and plasma terminal (?)
half-lives of 2.4, 18, and 360 h, respectively (J. S. Owen, S. M.
Bhavnani, J. Fiedler-Kelly, J. S. Loutit, S. B. Porter, and L.
Phillips, Abstr. 44th Intersci. Conf. Antimicrob. Agents Che-
mother., abstr. A-20, 2004).
Oritavancin has been shown to be effective in two phase 3
studies when dosed with either 200 mg or 1.5 to 3 mg/kg once
daily for 3 to 7 days for the treatment of patients with compli-
cated skin and skin structure infections (H. Giamarellou, W.
O’Riordan, H. Harris, S. Owen, S. B. Porter, and J. S. Loutit,
Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. L-739a, 2003; M. Wasilewski, D. Disch, J. McGill, H.
* Corresponding author. Mailing address: Cognigen Corporation,
395 Youngs Rd., Buffalo, NY 14221-5831. Phone: (716) 633-3463, ext.
257. Fax: (716) 633-7404. E-mail: email@example.com.
† Present address: Institute of Clinical Pharmacodynamics, Ordway
Research Institute, Albany, NY 12208.
Harris, W. O’Riordan, and M. Zeckel, Abstr. 41st Intersci.
Conf. Antimicrob. Agents Chemother., abstr. UL-18, 2001).
Inflammatory blister fluid models are useful for evaluating the
disposition of drugs into skin tissues and provide information
useful for dosage regimen decision support.
MATERIALS AND METHODS
Study design and methodology. This was an open-label, single-center study
designed to characterize the pharmacokinetic profile of oritavancin skin pene-
tration after administration of oritavancin via intravenous infusion in normal
healthy male subjects. Seventeen men ranging in age from 19 to 51 years (mean,
32 years), comprised of 13 Caucasians, 1 African-American, 2 Hispanics, and 1
subject of unknown ethnicity, were enrolled into the study. The study protocol
was approved by an institutional review board and all participants provided
written informed consent. Prior to the study, volunteers underwent complete
physical examinations and laboratory evaluations, including blood chemistries,
hematology, and urinalysis.
Blister induction and drug administration. Oritavancin was administered to
an initial group of eight subjects (group A) who received 200 mg per day infused
over 60 min for 3 consecutive days (total dose, 600 mg). After the group A
subjects completed all study assessments through day 12, a second group of nine
subjects (group B) received a single 800-mg dose of oritavancin infused over 90
min. On the evening before the third oritavancin dose for the group A subjects
and the evening before dosing for group B subjects, 0.2-ml drops of an ointment
containing 0.25% cantharidin powder (Sigma Laboratories, St. Louis, Mo.) and
standard ointment base were applied to the anterior forearms of the volunteers
to produce a total of four blisters per volunteer (3). The integrity of the blisters
was maintained by spraying them with a fast-drying plastic dressing (New-Skin
liquid bandage spray; Medtech Laboratories, Inc., Jackson, Wyo.). Additionally,
one blister was induced on the forearm at approximately 84 h and again at 132 h
after the start of the final oritavancin infusion to allow for blister exudate
collection at 96 and 144 h postdose, respectively. The 200-mg dosing scheme was
implemented in this study because it was the minimum dose that patients were
to receive in the phase 3 trials. The single 800-mg oritavancin dose regimen was
explored as it may be considered for future studies in patients with uncompli-
cated skin and skin structure infections. Routine safety monitoring was con-
ducted during and after oritavancin dosing in all subjects.
Pharmacokinetic sampling. Blood samples were collected into heparinized
Vacutainers from an indwelling catheter contralateral to that used for drug
administrations at predose and at 0.5, 1, 2, 4, 8, 12, 24, 96, and 144 h after the last
dose of oritavancin in each group. Simultaneously, exudate (100 to 200 ?l) from
cantharide-induced blisters was obtained. For plasma, additional samples were
collected at 216 h postdose. All samples were stored at ?80°C until assayed.
Samples were analyzed by a validated procedure in which oritavancin extraction
from plasma and blister fluid was accomplished by protein precipitation and
detection using a high performance liquid chromatography-tandem mass spec-
trometry assay. The lower limit of quantification (LLOQ) for skin blister fluid
and plasma was 1.25 and 0.075 ?g/ml, respectively. The interday variability of the
assay in plasma ranged from 3.8 to 6.3% over the concentration range of 0.075
to 2.5 ?g/ml.
Pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis was
performed using WinNonlin Pro, version 4.0 (Pharsight Corp., Mountain View,
Calif.), to generate pharmacokinetic parameter estimates for each oritavancin
dose group for both plasma and blister fluid. Parameter estimates included area
under the plasma and blister fluid concentration-time curve from time zero to
24 h (AUC0–24), area under the plasma and blister fluid concentration-time curve
from time zero to time t (the time of the last concentration above the LLOQ)
(AUC0-t), maximum concentration of drug in plasma or blister fluid (Cmax), and
tmax(time at which Cmaxoccurs). AUC was calculated using the linear trapezoi-
dal rule and Cmaxwas obtained directly from the experimental plasma and blister
concentration-time data, without interpolation.
Descriptive statistics, including the number of subjects (n), mean, geometric
mean, standard deviation (SD), coefficient of variation, and range, were calcu-
lated for each of the PK parameters in each oritavancin dose group for both
plasma and blister fluid. Drug concentrations at or below the LLOQ were treated
as zero for all calculations. The comparison of AUCblister fluidand AUCplasma
between dose groups was evaluated using a t test with a level of significance of
Noncompartmental pharmacokinetic parameters for plasma
and blister fluid are presented in Table 1. After the third day
of the 200-mg-per-day dosing regimen, the highest mean con-
centration of oritavancin was observed at approximately 1 and
10 h in plasma and blister fluid, respectively. At these time
points, the mean maximum drug concentration was approxi-
mately eightfold higher in plasma than in blister fluid. The
mean maximum plasma concentration was approximately 11-
fold greater than that in blister fluid after a single 800-mg dose
of oritavancin. Oritavancin levels decrease in blister fluid after
15 h and became undetectable 100 to 150 h after the last dose
(regardless of regimen). The mean plasma concentration of
oritavancin at 24 h was approximately 22% of the peak plasma
concentration in the 200-mg dose group compared with 14% in
the 800-mg dose group.
Mean AUCblister fluid/AUCplasmaratios at 24 h were 0.195
(SD, 0.053) and 0.185 (SD, 0.063) for the 200- and 800-mg dose
groups, respectively (P ? 0.730). Overall, the mean peak
plasma and blister fluid concentrations, along with the mean
values of AUC at 24 h, were greater in the 800-mg dose group
than with those receiving a cumulative dose of 600 mg (200 mg
for 3 days) (P of ?0.0001 for plasma Cmax, P of 0.0049 for
blister fluid Cmax, P of ?0.0001 for plasma AUC0–24, and P of
0.0019 for blister fluid AUC0–24) (Table 1). Mean concentra-
tion-time curves of oritavancin in plasma and blister fluid fol-
lowing the third 200-mg dose or the single 800-mg dose are
shown in Fig. 1 to 3. While no observed plasma concentrations
were at or below the LLOQ, a number of concentrations for
TABLE 1. Summary statistics for noncompartmental PK parameters for oritavancin in plasma and blister fluid
Mean result (SD) for plasma at dose:Mean result (SD) for blister fluid at dose:
200 mg QD, 3 daysd
800 mg, 1 day 200 mg QD, 3 days800 mg, 1 day
AUC0–24(?g ? h/ml)a
AUC0–t(?g ? h/ml)a
aPK parameter was tested for a difference between treatment groups.
bStatistically significant compared to the 800-mg dose group (P ? 0.005).
cNC, not calculated.
dQD, once a day.
VOL. 49, 2005PLASMA AND SKIN BLISTER FLUID PK OF ORITAVANCIN149
skin blister fluid were at or below the LLOQ (47/152). The
majority of these concentrations were collected at 24 h post-
dose. However, given that certain concentrations for skin blis-
ter fluid obtained at 0 to 2 h postdose were at or below the
LLOQ and thus assumed to be equal to zero, mean concen-
trations for these time points in Fig. 2 and 3 were lower than
Eight of 17 subjects enrolled (47%) experienced at least one
treatment-emergent adverse event. The incidence of adverse
events was 75% (6/8) in group A and 22% (2/9) in group B.
Adverse events were generally mild and transient in nature.
The most frequently reported adverse events were general
disorders and administration site conditions (group A, 50%
[4/8]; group B, 11% [1/9]). One subject in each group experi-
enced a moderate adverse event, one of which was injection
site thrombosis, possibly related to study drug, while the other
FIG. 1. Mean oritavancin concentration versus time in plasma following the third 200- or one 800-mg dose. Circles, 200-mg dose; squares,
800-mg dose. Each sample represents the mean ? SD; n ? 8.
FIG. 2. Mean oritavancin plasma and blister fluid concentrations versus time during the 24 h following the third 200-mg dose. Circles,
oritavancin in plasma; squares, oritavancin in blister fluid. Each sample represents the mean ? SD; n ? 8.
150 FETTERLY ET AL.ANTIMICROB. AGENTS CHEMOTHER.
was muscle spasms, probably not related to study drug. There
were no severe adverse events, study deaths, or premature
study withdrawals associated with an adverse event.
Increasing antimicrobial resistance among aerobic gram-
positive bacteria is a global concern. National rates of methi-
cillin-resistant Staphylococcus aureus (MRSA) have been re-
ported to generally range from 30 to 50%, with rates as high as
70% (2). Staphylococci remain the leading cause of compli-
cated skin and skin structure infections. The high prevalence of
MRSA has limited the utility of traditional treatment modal-
ities, and today, relatively few treatment options remain avail-
able to the clinician when resistant pathogens are encountered.
Oritavancin, a novel glycopeptide antimicrobial agent with in
vitro activity against multidrug resistant gram-positive bacteria,
including MRSA (R. S. Blosser, J. S. Loutit, S. B. Porter, R. K.
Flamm, and D. F. Sahm, Abstr. 43rd Intersci. Conf. Antimicrob.
Agents Chemother., abstr. C1-1636, 2003; R. S. Blosser, S. B.
Porter, D. F. Sahm, and J. S. Loutit, Abstr. 43rd Intersci. Conf.
Antimicrob. Agents Chemother., abstr. C1-1637, 2003; D. F.
Sahm, R. S. Blosser, J. S. Loutit, and S. B. Porter, Abstr. 43rd
Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1640,
2003), is being developed for the treatment of complicated skin
and skin structure infections. This study was conducted to com-
pare oritavancin exposure in the interstitial space fluids of soft
tissues (i.e., the relevant target site) with that of plasma using a
cantharidin-induced skin blister fluid model.
A key observation from this study concerns the residence
time of oritavancin in skin blister fluid. Oritavancin levels are
maximal in blister fluid 10 h after dosing and decrease to
undetectable levels 100 to 150 h after the last dose. This is
consistent with what is currently understood about the phar-
macokinetics and tissue distribution of oritavancin, namely,
that tissue residence time is generally shorter in tissues such as
skin that are not rich in macrophages. In addition, this obser-
vation is consistent with the general lack of late-onset drug-
related adverse events in clinical studies.
Our main finding was that total-drug oritavancin exposure in
interstitial fluids was approximately 19% of that in plasma,
regardless of dosing regimen. Since drug concentration in in-
terstitial fluid exists in equilibrium with the unbound plasma
fraction, one would expect the oritavancin exposure in inter-
stitial fluid from noninflamed tissue to be similar to that of
free-drug exposure in plasma. Approximately 13% of oritavan-
cin is unbound to plasma proteins (P. A. Rowe and T. J.
Brown, Abstr. 41st Intersci. Conf. Antimicrob. Agents Che-
mother., abstr. A-2193, 2001). Thus, for the 200-mg regimen,
an AUCblister fluid/AUCplasmaratio (90.7/457) of 0.19 translates
to an AUCblister fluid/AUCfree plasmaratio (90.7/59.4) of approx-
imately 1.5. Given that the cantharidin-induced skin blisters
are derived via chemical irritation, it appears that there is a
modest accumulation of oritavancin in the presence of inflam-
Our observations are consistent with findings from studies
comparing the microdialysis (a noninflammatory model) and
cantharidin-induced skin blister fluid models for estimating
drug exposure in interstitial fluids. Mu ¨ller and colleagues (4)
compared moxifloxacin concentrations in cantharidin-induced
skin blisters and interstitial fluid obtained via microdialysis in a
study with a crossover design. After oral administration, the
AUCfree plasmaratios were approximately 0.84 and 1.3, respec-
The mechanism of the potential preferential oritavancin dis-
tribution to inflamed tissue is unknown. The most likely hy-
pothesis involves macrophages, as oritavancin has been shown
to be concentrated in macrophages, which migrate to inflamed
tissues (F. Van Bambeke, H. Chanteux, D. Tyteca, M. P. Min-
geot-Leclercq, and P. M. Tulkens. Abstr. 43rd Intersci. Conf.
Antimicrob. Agents Chemother., abstr. A-1169, 2003). Further
plasmaand AUCblister fluid/
FIG. 3. Mean oritavancin plasma and blister fluid concentrations versus time during the 24 h following the 800-mg dose. Circles, oritavancin
in plasma; squares, oritavancin in blister fluid. Each sample represents the mean ? SD; n ? 8.
VOL. 49, 2005PLASMA AND SKIN BLISTER FLUID PK OF ORITAVANCIN 151
study may be warranted to evaluate the potential preferential Download full-text
distribution of oritavancin to inflamed tissue.
Two of the most important factors that affect the adequacy
of an antimicrobial regimen are the drug exposure observed in
a patient and how susceptible the infecting pathogen is to the
agent selected for therapy (6). Integration of these two param-
eters may be described pharmacodynamically. Outcomes of
infection in nonclinical infection models (in vitro and animal)
and human studies usually correlate with at least one of three
pharmacokinetic-pharmacodynamic (PK-PD) measures: (i)
proportion of the dosing interval at which concentrations of an
antimicrobial agent exceeds the MIC of the agent against the
pathogen (percent time?MIC); (ii) ratio of the peak concen-
tration of the antimicrobial agent to the MIC of the agent
against the pathogen (Cmax:MIC); and (iii) ratio of the AUC to
the MIC of the agent against the pathogen (AUC:MIC).
The pharmacodynamic profile of oritavancin has been char-
acterized in vitro and in animal infection models. Oritavancin
displays a concentration-dependent pattern of bactericidal ac-
tivity in vitro against a wide variety of pathogens commonly
associated with complicated skin and skin structure infections,
including methicillin-susceptible and -resistant S. aureus (D. F.
Sahm, R. S. Blosser, J. S. Loutit, and S. B. Porter, Abstr. 43rd
Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1170,
2003). Boylan et al. studied the PK-PD of oritavancin in a
neutropenic-mouse thigh model of S. aureus infection (1a).
The endpoint for efficacy was the change in bacterial density at
24 h. The results of this study demonstrated a strong associa-
tion between both free-drug Cmax:MIC ratio and free-drug
time?MIC and reduction in bacterial density (r2? 0.93 and
0.84, respectively). Bacterial stasis was associated with a free-
drug Cmax:MIC ratio of approximately 6 and percent free-drug
time?MIC of approximately 17 to 20%. Near maximal effect
associated with a greater than 90% reduction in bacterial den-
sity (?1- to 1.5-log reduction in bacterial density) was achieved
with a free-drug Cmax:MIC ratio of approximately 14 and per-
cent free-drug time?MIC of approximately 42 to 50%.
A subsequent analysis of clinical data from a phase 3 study
of oritavancin in patients with S. aureus bacteremia supported
the findings of a exposure-response relationship with free-drug
percent time?MIC and microbiological response. A classifica-
tion and regression tree-defined breakpoint of 22% free-drug
time?MIC was identified for microbiological response; the
probability of success greater than or equal and less than this
value was 93 and 76%, respectively (S. M. Bhavnani, J. A.
Passarell, J. S. Owen, J. S. Loutit, S. B. Porter, and P. G.
Ambrose, Abstr. 44th Intersci. Conf. Antimicrob. Agents Che-
mother., abstr. A-1475, 2004).
Integration of the above-described PK-PD targets associated
with efficacy from exposure-response analyses based on both
animal and clinical data with oritavancin exposure data from
the present analysis requires consideration of the MIC distri-
bution for oritavancin against target pathogen(s) and the im-
pact of oritavancin plasma protein binding on available drug
concentrations. Given that the oritavancin MIC at which 90%
of strains are inhibited (MIC90) for methicillin-susceptible and
-resistant S. aureus is 2.0 ?g/ml (Blosser et al., 43rd ICAAC)
and that approximately 13% of oritavancin is unbound to
plasma proteins (P. A. Rowe and T. J. Brown, Abstr. 41st
Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-2193,
2001), mean free-drug plasma concentrations associated with
the 200-mg and 800-mg regimen exceeded the MIC90over
close to the entire dosing interval (percent free-drug
time?MIC greater than or equal to 92%).
Although the extent of protein binding of oritavancin is
understood in plasma, the extent of binding in blister fluid is
not as clear. While further studies may be required to elucidate
this issue, inferences may be drawn from previous studies eval-
uating the relationship between free-drug in plasma and blister
fluid. Data from both Wise (7) and Redington et al. (6) dem-
onstrated a close approximation between free-drug plasma and
blister fluid AUC values for a number of ?-lactam agents, thus
suggesting comparatively less protein binding in blister fluid. If
the same relationship was true for oritavancin plasma and skin
blister exposures, one would expect concordance between free-
drug concentrations in plasma (based on a protein binding
assumption of 87%) and total-drug concentrations in blister
fluid. Indeed, free-drug extrapolated concentrations in plasma
are close to or less than total-drug concentrations in blister
fluid. Assuming that free-drug concentrations in plasma equal
that of blister fluid or that a high proportion of the total
concentrations in blister fluid are free, a percent free-drug
time?MIC of 22% or higher would be expected for a 200-mg
regimen in most patients.
These data demonstrate that after administration of orita-
vancin at 200 mg once daily for 3 days or 800 mg as a single
dose, blister fluid concentrations for total drug exceed the
MIC90of oritavancin against S. aureus. Moreover, for either
oritavancin regimen, percent free-drug time?MICs associated
with in vivo efficacy are exceeded in plasma. Together, these
findings buttress the selection of the 200-mg once daily regi-
men and support oritavancin as a potential therapeutic modal-
ity for complicated skin and skin structure infections.
We thank Julie Passarell for statistical support.
We thank InterMune, Inc., for financial support of this study.
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