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Antimicrobial Agents and Chemotherapy, March 2001, p. 917-921, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.917-921.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacokinetics of a New Parenteral Oligosaccharide Antibiotic,
SCH27899 (Ziracin), in Healthy Subjects
Osamu
Kozawa,1
Toshihiko
Uematsu,1,*
Hiroyuki
Matsuno,1
Masayuki
Niwa,1
Ken-Ichi
Kohno,2
Asakazu
Kawato,3
Kazuyoshi
Takahashi,3
Satoru
Nagashima,2 and
Mitsutaka
Kanamaru2
Department of Pharmacology, Gifu University School of
Medicine, Gifu 500-8705,1 Shitoro
Clinic, Hamamatsu 432-8066,2 and R & D Division, Clinical Development Department, Schering-Plough KK, Osaka
541-0046,3 Japan
Received 13 April 2000/Returned for modification 8 October
2000/Accepted 26 December 2000
 |
ABSTRACT |
The pharmacokinetic properties of an everninomicin antibiotic
(SCH27899; Ziracin) were studied with healthy Japanese male volunteers
by single (1, 3, 6, and 9 mg/kg of body weight) and multiple 60-min
intravenous infusions (3, 6, and 9 mg/kg once daily for 10 consecutive
days following a 2-day interval after the initial dose). At single
doses the peak serum concentration and the area under the serum
concentration-time curve linearly increased with the dose. While total
body clearance (CL; 31.2 to 45.6 ml/kg/h) and percent cumulative
urinary recovery as unchanged drug (4.9 to 7.1%) were rather constant
irrespective of doses, the terminal half-life of 
phase
(t1/2
; 14.2 to 19.6 h) were slightly
prolonged at the higher two doses compared with the lower two doses.
With repeated doses of SCH27899, a statistically significant decrease
and increase were found in CL and t1/2 of
about 36 and 21%, respectively, although these changes may be
clinically irrelevant. The most commonly reported adverse events were
local reactions such as erythema, pain, and palpable venous cord
of mild to moderate degree around the injection site, which could be
managed by changing the injection sites.
| |
INTRODUCTION |
Gram-positive cocci have reemerged
as important nosocomical pathogens around the world, especially in the
last decade (8). To combat increasing penicillin
resistance among pneumococci and viridant streptococci, active agents
against such pathogens are increasingly needed, particularly under the
threat of the emergence of those resistant to vancomycin and
structurally related teicoplanin (3, 11, 13).
SCH27899,
O-(1R)-4-O-(2,4-dihydoxy-6-methylbenzoyl)-2,3-O-methylene-D-xylopyranosylidene-(1
3-4)-
-L-lyxopyranosyl-O-2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro--L-arabino-hexopyranosyl-(13)-O-2,6-dideoxy-4-O-(3,5-dichloro-4-hydroxy-2-methoxy-6-methylbenzoyl)-
-D-arabino-hexopyranosyl-(14)-O-2,6-dideoxy-D-arabino-hexopyranosylidene-(13-4)-O-6-deoxy-3-C-methyl--D-mannopyranosyl-(13)-O-6-deoxy-4-O-methyl-D-galactopyranosyl-(14)-2,6-di-O-methyl-D-mannopyranoside (Ziracin), is an oligosaccharide, everninomicin antibiotic
with activity primarily against gram-positive pathogens including
glycopeptide-resistant enterococci, oxacillin-resistant
staphylococci, and penicillin-resistant streptococci and
pneumococci (6).
In the present study the pharmacokinetics and tolerability of SCH27899
were studied with healthy Japanese male volunteers to obtain
information to guide the rational use of this agent for the patients.
This paper reports that it was possible at proposed clinical doses to
attain serum concentrations high enough to exceed the MICs and
MIC90s for various clinical isolates (7, 10, 12), including multiresistant staphylococci and enterococci, and
that safety will be maintained for patients at those doses.
| |
MATERIALS AND METHODS |
Volunteers.
Before the implementation of this study, the
research protocol and the consent form were reviewed and approved by
the Ethics Committee of Shitoro Clinic, 5332-1 Shitoro-cho, Hamamatsu,
Japan. Volunteers were selected on the basis of physical examination, medical history, and screening laboratory tests. Sixty-three healthy male subjects aged 24.1 ± 4.0 (mean ± standard deviation
[SD]; range, 20 to 37) years and weighing 64.0 ± 8.0 (51.4 to
79.4) kg participated in the study after giving informed consent. Each subject received only one treatment regimen with a SCH27899 or placebo infusion.
Study protocol.
The primary objective of this study was to
evaluate the safety and tolerability of SCH27899. With six volunteers
receiving treatment in each treatment group, there was an 80% chance
of at least one occurrence of any untoward event with an incidence rate
of 25%.
The pharmacokinetics and safety were first examined by single
intravenous administrations of SCH27899 (1, 3, 6, and 9 mg/kg of body
weight) in a dose-escalating manner. At each dose, six and three
subjects received SCH27899 dissolved in dextrose and placebo (dextrose
only), respectively, by a single-blind method. Venous blood samples (5 ml) were collected before (0 h) and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 144 h after the start of 60-min intravenous infusion.
Urine was collected as voided just before administration, which served
as a blank for measurement, and at intervals of 0 to 4, 4 to 8, 8 to
12, 12 to 24, and 24 to 48 h after the beginning of drug
administration. The repeated-dose study (3, 6, and 9 mg/kg) was also
conducted in a dose-escalating manner. At each dose, six and three
subjects received a single 60-min infusion of SCH27899 dissolved in
dextrose and of placebo (dextrose only), respectively, by a
single-blind method on day 1. After a 2-day interval, the same
treatment was administered once daily for 10 consecutive days from day
4 to day 13. Venous blood samples were also obtained in the same manner
as in the single-dose study on days 1 and 13. Additionally, blood was
withdrawn from each subject just before each dose, at the end of
infusion on days 5 and 8, and 7 days after the last administration.
Urine was collected in the same manner as in the single-dose study on days 1 and 13 and additionally as 24-h block samples on the other dosing days and for 3 days after the last administration.
All subjective and objective symptoms either observed by the
investigators or reported by the subject spontaneously or in
response
to a direct question were recorded. If any adverse event
occured after
dosing, the subject was followed with appropriate
treatment and close
medical supervision. Casualty and severity
ratings were determined. In
the single-dose study, blood biochemistry
and hematology tests,
urinalysis, and an electrocardiogram were
performed at screening,
before administration, and 24 h, 7 days,
and 14 days after
administration. Vital signs including body temperature
and blood
pressure were monitored just before and periodically
up to 48 h
after administration. In the multiple-dose study, blood
biochemistry
and hematology tests, urinalysis, and an electrocardiogram
were
performed at screening, before dosing, and 24 h after dosing
on
days 1, 2, 4, 7, and 10, and 7 days after the end of dosing.
Vital
signs were monitored just before the first administration
and
periodically up to 48 h after the last
administration.
Assays.
The 4-ml blood samples collected in the course of
the study were allowed to stand at room temperature for 30 min and then centrifuged at 1,500 × g for 15 min at 4°C. The
separated sera were transferred into plastic tubes. The volume of
time-block urine samples was measured, and 0.5 ml of 1 M sodium
dihydrogenphosphate (pH 6.9) and 5 ml of acetonitrile were added to
urine aliquots (5 ml). These serum and buffered urine samples were
stocked at 
20°C until analyzed. Serum and urinary concentrations
of SCH27899 were determined by validated high-performance liquid
chromatography (HPLC) using thiabendazole as an internal standard (IS).
An aliquot (250 µl) of serum, calibration standard, or quality
control (QC) sample was well mixed with 50 µl of IS solution in
methanol (5 µg/ml) in a centrifugation tube to which was added 500 µl of acetonitrile. The mixture was centrifuged at approximately
2,700 × g for 10 min at 20°C. The supernatant was
transferred to another tube and the solvent was evaporated under
nitrogen gas flow at about 40°C. The residue was reconstituted with
200 ml of 50 mM sodium dihydrogenphosphate (pH 6.9) and acetonitrile
(1:1, vol/vol). The resolubilization was followed by centrifugation at
approximately 4,400 × g for 5 min at room temperature.
An aliquot (75 µl) of the supernatant was injected onto an HPLC. For
urine, the calibration curve was prepared using blank human urine, 1 M
sodium dihydrogenphosphate, and acetonitrile (100:1:100, vol/vol/vol)
supplemented with 200 to 50,000 ng of SCH27899/ml. The QC samples were
prepared at 500, 20,000, and 40,000 ng of SCH27899/ml. To an aliquot (1 ml) of buffered urine, calibration standard, or QC sample, 50 µl of
IS in methanol (25.0 µg/ml) was added. After agitation, the mixture was centrifuged at approximately 4,400 × g for 5 min
at room temperature. An aliquot (75 µl) of the supernatant was
injected onto the HPLC. The HPLC system (Hitachi, Tokyo, Japan)
consisting of a pump (L-7100), an autosampler (L-7200), and a UV
detector (L-7400; wavelength, 300 nm). A computerized data acquisition
system (DESKPRO, Compaq, Tokyo, or FLORA3010DU II, Hitachi, Tokyo,
Japan) was used for integration of peak heights and calculation of
data. An octyldecyl silane analytical column (Asahipak ODP-50; 4.6 mm
ID by 150 mm; Showadenko, Tokyo, Japan) was used. The mobile phase was
a mixture of 20 mM sodium dihydrogenphosphate (pH 7.8) and acetonitrile (31:21, vol/vol). The solution was filtered through a membrane filter
(pore size; 0.45 µm) and degassed before use. The HPLC system was
operated at ambient temperature. The flow rate was 1.0 ml/min.
The calibration curve for serum assay was prepared ranging to 50,000 ng
of SCH27899/ml. The HPLC peak height ratio (SCH27899/IS,
y)
versus SCH27899 concentration (
x) data from the calibration
curve constructed were evaluated using a linear equation for each
calibration curve (
y = a
x + b) by
weighed (1/
x) least-squares
regression for both serum and
urine samples. The lower limit of
quantitation was established at 50 and 200 ng/ml for serum and
urine samples, respectively. The QC samples
were prepared at 150,
25,000, and 40,000 ng/ml. In serum, the
within-day precision (%
coefficient of variation) ranged from 1.6 to
5.3% at the three
concentrations (0.150, 4.00, and 40.0 µg/ml) on
all three validation
days (days 1, 2, and 3), and the between-day
precision values
obtained for the samples of these concentrations were
13.8, 4.7,
and 4.2, respectively, on five different days. In urine, the
within-day
precision ranged from 0.9 to 3.7% at three concentrations
(0.600,
6.0, and 40.0 µg/ml) on all three validation days, and the
between-day
precision values were 2.6, 3.7, and 4.6%, respectively, on
three
different days. Results for the standards and QC samples met the
criteria for acceptable performance of the method during the
period
of study sample
analysis.
Pharmacokinetic and statistical analyses.
As compared to a
two-compartment open model, serum concentrations of SCH27899 apparently
fitted much better to a three-compartment open model, especially around
the peak concentration and declining phase, with lower Akaike's
Information Criterion values (data not shown), and therefore were
individually analyzed with this model by employing the nonlinear
least-squares computer program (WinNonlin). The half-lives of , ,
and phases (t1/2
, t1/2
, and t1/2),
distribution volume at steady state (Vss), and
total body clearance (CL) were determined according to this analysis.
The peak serum concentration was obtained from the direct measurement
of serum concentration obtained at the end of a 60-min intravenous
infusion (C1h). The area under the serum concentration-time
curve from time 0 to the final quantifiable concentration-time point
(AUC0-t) and AUC to 24 h (AUC0-24) were
calculated by using the linear trapezoidal rule. The AUC extrapolated
to infinity (AUC0-
) was obtained by a combination of
the trapezoidal rule until the time of the last quantifiable serum
concentration and extrapolation to infinity by using the quotient of
the last measurable concentration to the terminal-phase rate constant,
which was calculated as the negative of the slope of the log-linear
terminal portion of the serum concentration-time curve using linear regression.
The pharmacokinetic parameters thus obtained were log transformed prior
to any statistical analysis. Means of the pharmacokinetic
parameters
obtained from the single-dose study were compared among
the doses by
Scheffe's multiple comparison after excecuting analysis
of variance.
Those from the repeated-dose study were compared
between the first and
last doses by Student's paired
t test.
P values
less than 0.05 were considered to be
significant.
| |
RESULTS |
In the single-dose study, SCH27899 was well tolerated with no
injection-site reactions. With repeated administrations of 3 mg of
SCH27899/kg, such injection site reactions as erythema, pain, and
palpable venous cord of mild to moderate degree were reported from day
5 by three of six subjects. However, these local reactions could be
avoided or managed by changing the injection sites, so that the final
incidence of local reactions was three of six, one of six, and two of
six subjects at the doses of 3, 6, and 9 mg/kg, respectively. In a
subject in the 6 mg/kg repeated-dose group, the drug was discontinued
during the sixth consecutive dose because of the appearance of a skin
rash with itching of moderate degree near the end of infusion.
Immediately after the discontinuation of drug infusion, the skin rash
started to rapidly disappear. This subject was excluded from the final
data analysis. Desquamation of the fingertips of mild degree was noted
in two of six subjects after the completion of the highest repeated doses.
Fig. 1 describes the time profiles of
SCH27899 concentration in serum in the single-dose study, and key
pharmacokinetic parameters calculated using the actual values are
summarized in Table 1. Serum
concentrations were individually analyzed by a three-compartment open
model except in the case of one subject who received the lowest dose.
Accordingly, model-dependent parameters in Table 1 were calculated and
compared by excluding this subject. C1h and
AUC0- were increased in proportion to the dose (Fig.
2), while t1/2
was prolonged at the higher two doses as compared with the lower two
doses and CL tended to be decreased with the dose (Table 1). The
urinary recovery of unchanged drug was almost the same irrespective of
dose: 4.87 ± 1.16, 4.97 ± 0.90, 7.05 ± 0.69, and 6.48 ± 0.80% at the doses of 1, 3, 6, and 9 mg/kg, respectively. Fig.
3 shows the time profiles of SCH27899 concentration in serum in association with repeated doses, and key
pharmacokinetic parameters calculated using the actual values are
summarized in Table 2. Then, the
parameters obtained for the first dose were compared with those for the
last dose. Significant increases of 13 to 22% were found in AUC, which
means a net accumulation in the body at steady state, when
AUC0- after the first dosing was compared with
AUC0-24 after the last one. At the same time, the CL was
decreased by approximately 36% and the elimination half-life was
prolonged by 20 to 23% (Table 2). The final urinary recovery of
unchanged drug by 72 h after the last dose was 7.54 ± 0.97, 8.40 ± 1.08, and 9.12 ± 1.43% at the repeated doses of 3, 6, and 9 mg/kg, respectively.
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FIG. 1.
Time profile of the serum concentration of
SCH27899 after single intravenous 60-min infusions of 1 ( ), 3 ( ),
6 ( ), and 9 ( ) mg/kg.
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FIG. 2.
Relationship beween the single dose of SCH27899 and the
serum concentration at the end of a 60-min infusion (C1h,
) or the area under the serum concentration curve from 0 h to
infinity (AUC0-,  ).
|
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FIG. 3.
Time profile of the serum concentration of SCH27899 in
association with repeated intravenous 60-min infusions of 3 (), 6 (), and 9 () mg/kg. At a 2-day interval after a single infusion
on day 1, the same infusion dose was repeated once daily for 10 consecutive days from day 4 through day 13.
|
|
| |
DISCUSSION |
The present study revealed pharmacokinetic properties of SCH27899
in healthy subjects which support the feasibility of once-daily administration for clinical practice.
In the single-dose study, the C1h and AUC increased in
proportion to the dose within the dose range examined (1 to 9 mg/kg; Fig. 2). The percent cumulative urinary recovery as unchanged drug was
less than 10% irrespective of dose, showing that the main route of
excretion of SCH27899 is extrarenal, through biotransformation by the
liver. At the lowest dose the terminal () phase of serum concentration could not be fully described due to the methodological imbalance between the actual concentration and the detection limit for
measurement. In fact, an attempt for a subject of the lowest dose group
to fit his serum concentrations of SCH27899 by a three-compartment open
model failed with no convergence because of the lack of information on
the terminal phase. As judged from the above finding together with the
observation that the CL remained almost unaltered within the dose range
of 3 to 9 mg/kg, the possibility that the hepatic capacity to
biotransform this agent might be saturated around the present dose
range would not be the case, although the
t1/2 was significantly prolonged at the
higher two doses compared with the lower two doses. On the other hand,
in association with repeated administrations of SCH27899, a
statistically significant decrease and increase were found in the CL
and t1/2 of about 36 and 21%, respectively,
resulting in a significant increase in the AUC of about 17%. Although
these changes may be clinically irrelevant, precaution should be taken
against some possible abnormal accumulation of SCH27899 in the body
with repeated administrations, especially in patients with impaired
hepatic function.
There were no clinically significant dose-related changes in hepatic or
renal function tests or clinical assessments that might hinder further
clinical development. However, the injection-site reactions of mild to
moderate degree and the adverse events of skin rash and fingertip
desquamation, which might be due to some allergic reactions and should
be carefully investigated in further study, should urge us to assess
the ratio of risk to benefit of the actual use of this agent in patients.
The glycopeptide antibiotic vancomycin and the structurally related
antibiotic teicoplanin have been considered to be the last lines of
defense against a variety of serious infections caused by gram-positive
organisms such as enterococci and staphylococci (9, 11).
The recent rapid emergence and spread of vancomycin-resistant enterococci (VRE) is, therefore, of grave concern to both medical practioners and their patients. Reports of the extensive spread of
vancomycin-resistant, i.e., heteroresistant, MRSA
(methicillin-resistant Staphylococcus aureus) strains in
Japanese hospitals after 30 years of vancomycin use as the drug of
choice for the treatment of MRSA are of particular concern in light of
observations that the high-level VanA vancomycin resistance
gene can be transferred from enterococci to staphylococci in vitro
(1). To reduce the spread of VRE and other multiresistant
bacteria such as heteroresistant MRSA and drug-resistant
Streptococcus pneumoniae, the clinical development of safe
and effective innovative agents should be promoted and an aggressive
infection and antibiotic control strategy established (3).
For example, the development of new glycopeptides, including LY264826
and its semisynthetic derivative LY333328, is of special interest
because of their potential usefulness in the treatment of VRE
infections (2). However, these agents are not necessarily
free from potential cross-resistance with vancomycin and teicoplanin.
SCH27899 is structurally different from vancomycin or teicoplanin
(6, 7, 10). The results obtained in preclinical studies of
SCH27899, suggesting a promising safety and efficacy profile, together
with the clinical need for this kind of agent have led us to conduct
the present study using healthy Japanese subjects to clarify its
pharmacokinetic characteristics in humans. Its main route of excretion
is extrarenal, in contrast to the renal route with vancomycin and
teicoplanin (9, 15). Therefore, this agent could be used
more safely than vancomycin or teicoplanin in patients with impaired
renal function.
A decrease in CL of around 30% has been reported for vancomycin at
steady state as compared with initial therapy (14).
Although vancomycin is considered to be excreted exclusively through
the renal route, this is explained by the decrease in hepatic
biotransformation in light of some reports that vancomycin could
display a significant metabolism (4). In the present study
of SCH27899, a similar decrease in CL of 36% was also noted at steady state.
Since preclinical studies indicate that the MICs of SCH27899 for most
gram-positive strains of clinical isolates, including multiresistant
staphylococci and enterococci, range from 0.015 to 1.0 µg/ml with
MIC90s of 0.12 to 0.5 µg/ml (7, 10, 12), it
is one of the essential factors for clinical utilization that the
C1h exceeds these MIC and MIC90 values. As seen
from Fig. 3, the plasma concentration of SCH27899 above around 1.0 µg/ml could be maintained for 12 to 48 h by the administration
of 3 to 9 mg/kg, depending on the dose. Vancomycin is reported to have a postantibiotic effect (PAE) of 2 to 3 h against S. aureus (5), and teicoplanin is shown to have an even
longer PAE than vancomycin (16). SCH27899 is also
considered to have a PAE of a little longer than vancomycin
(unpublished observation). Therefore, on the basis of the present
observations on pharmacokinetics and safety, the once-daily regimens of
3 to 9 mg of SCH27899/kg should be tested in further clinical
investigation even against multiple-resistant gram-positive bacterial
infections. This study was carried out using healthy male Japanese
volunteers only, and more data may be needed for treatment of actual
patients or females, especially to explore the relationship between
serum concentration and clinical efficacy.
| |
ACKNOWLEDGMENT |
This work was supported in part by the Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, Sports and
Culture of Japan.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pharmacology, Gifu University School of Medicine, 40 Tsukasa-machi,
Gifu 500, Japan. Phone: 81-58-267-2231. Fax: 81-58-267-2959. E-mail: uematsu{at}cc.gifu-u.ac.jp.
| |
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Antimicrobial Agents and Chemotherapy, March 2001, p. 917-921, Vol. 45, No. 3
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.3.917-921.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
