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Antimicrobial Agents and Chemotherapy, June 1998, p. 1433-1436, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Pharmacokinetics and Safety of a New Parenteral
Carbapenem Antibiotic, Biapenem (L-627), in Elderly Subjects
Osamu
Kozawa,1
Toshihiko
Uematsu,1,*
Hiroyuki
Matsuno,1
Masayuki
Niwa,1
Yoshiharu
Takiguchi,2
Syouzou
Matsumoto,3
Masahiko
Minamoto,3
Yoshito
Niida,3
Masahiro
Yokokawa,3
Satoru
Nagashima,4 and
Mitsutaka
Kanamaru4
Department of Pharmacology, Gifu University
School of Medicine, Gifu 500,1
Department of Clinical Pharmacology, Graduate School of
Pharmaceutical Sciences, The Tokushima University, Tokushima
770,2
Lederle Japan Ltd., Tokyo
175,3 and
Shitoro Clinic, Hamamatsu
432,4 Japan
Received 19 May 1997/Returned for modification 10 November
1997/Accepted 24 March 1998
 |
ABSTRACT |
The pharmacokinetics and tolerability of a new parenteral
carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 ± 2.7 years
[mean ± standard deviation], n = 5; group B)
and 
75 years (77.8 ± 1.9 years, n = 5; group
C), following single intravenous doses (300 and 600 mg), and compared
with those of healthy young male volunteers aged 20 to 29 years
(23.0 ± 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the
dose in all three groups. Statistically significant age-related effects
for AUC, total body clearance, and renal clearance (CLR) were found, while elimination half-life
(t1/2
) and percent cumulative recovery from
urine of unchanged drug (% UR) remained unaltered
(t1/2, 1.51 ± 0.42 [300 mg] and
2.19 ± 0.64 [600 mg] h [group A], 1.82 ± 1.14 and
1.45 ± 0.36 h [group B], and 1.75 ± 0.23 and
1.59 ± 0.18 h [group C]; %UR, 52.6% ± 3.0% [300 mg]
and 53.1% ± 5.1% [600 mg] [group A], 46.7% ± 7.4% and 53.0% ± 4.8% [group B], and 50.1% ± 5.2% and 47.1% ± 7.6% [group
C]). A significant linear correlation was observed between the
CLR of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to
be decreased with age, although not significantly. Therefore, the
age-related changes in parameters of biapenem described above were
attributable to the combination of decreased lean body mass and lowered
renal function of the elderly subjects. However, the magnitude of those
changes does not necessitate dosage adjustment in elderly patients with
normal renal function for their age.
| |
INTRODUCTION |
Biapenem,
(1R,5S,6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a] [1,2,4]
triazolium-6-yl)]-thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate L-627, is a new parenteral carbapenem developed by Lederle
(Japan), Ltd. It exhibits antibacterial activity against a wide range
of gram-positive and -negative bacteria (14). It is
also stable to human renal dehydropeptidase I and therefore does not
require the coadministration of a dehydropeptidase I enzyme inhibitor (6).
Single and repeated intravenous doses of biapenem have been shown to be
well tolerated in healthy young volunteers, with linear pharmacokinetics exhibited within the dosage range of 20 to 600 mg
(9). In normal subjects, biapenem is cleared primarily by urinary excretion. The predominant concern in terms of adverse reactions to the prototype carbapenem antibiotic, imipenem/cilastatin, is the greater tendency to cause seizures than that of other
-lactams. The risk of producing a seizure is highly associated with
inadequate dose adjustment in relation to renal function
(1).
In general, it is accepted that adverse drug effects are more
frequently encountered in the elderly. The heightened susceptibility to
adverse reactions is due to a number of factors, including altered
pharmacokinetic properties of many drugs (12, 15, 16). It is
well recognized that many physiologic functions including renal
function diminish with increasing age (3, 13). In
consideration of these observations, full clarification of
pharmacokinetic properties of biapenem in the aged is quite essential
for its safe application to them.
In the present study, the pharmacokinetics of biapenem were
investigated in an elderly population and compared with those of
healthy younger subjects. Our results will aid physicians in adjusting
the dosage of the new carbapenem antibiotic for this age group.
| |
MATERIALS AND METHODS |
Subjects and study protocols.
Before the implementation of
this study, the research protocol and the consent form were reviewed
and approved by the Ethics Committee of Shitoro Clinic, Hamamatsu,
Japan. Volunteers were selected for enrollment in the study on the
basis of physical examination, medical history, and clinical laboratory
tests performed prior to the drug administration. In addition, elderly
subjects were enrolled in the study on the basis of criteria such as
being self-supporting and medically stable under restriction of other medications for 1 week prior to the beginning of study. Finally, 5 younger healthy male subjects (group A) aged 23.0 ± 3.5 years (mean ± standard deviation [SD]; range, 20 to 29 years) and
weighing 59.4 ± 7.2 kg and 10 elderly subjects (three males and
seven females) participated in the present study after giving their
written informed consent. The elderly subjects were subdivided into two
groups based on two age ranges, 65 to 74 years and 75 years, namely, group B (71.6 ± 2.7 years, 55.6 ± 7.5 kg of body weight,
n = 5) and group C (77.8 ± 1.9 years, 56.5 ± 11.4 kg of body weight, n = 5). Caffeine-containing
beverages and smoking were prohibited from 12 h before until
24 h after drug administration. Use of other medications was
restricted from 7 days before until 24 h after drug
administration.
The safety and pharmacokinetics were examined by single intravenous
dosing of biapenem over 1 h. Biapenem was administered first at
the dose of 300 mg and then at the dose of 600 mg at a 1-week interval.
On each study day, biapenem was administered to the volunteers after
overnight fasting. Venous blood samples (5 ml) were collected in
heparinized tubes before (0 h) and 1, 1.25, 1.5, 2, 3, 5, 9, 12, and
24 h after the beginning of the 1-h intravenous administration.
Urine samples were collected as voided just before administration, and
at intervals of 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to
24 h after the beginning of drug administration.
Plasma was immediately separated from the blood samples by
centrifugation at 1,500 × g for 5 min under cooling.
The plasma sample was mixed with the same volume of 1 M
3-(N-morpholino)propanesulfonic acid (MOPS) buffer (pH 7.0),
immediately frozen in methyl alcohol with dry ice, and stored at
80°C until analyzed. The volume of urine sample from each time
period was measured accurately. An aliquot (5 ml) was mixed with the
same volume of 1 M MOPS buffer (pH 7.0), frozen in the same manner as
the plasma sample, and stored at 80°C until analyzed.
All subjective and objective symptoms either observed by the
investigators or reported by the subject spontaneously or in
response
to a direct question were noted. If any adverse experience
occurred
after the administration of each test drug, the subject
was to be given
appropriate treatment and close medical supervision.
Causality and
severity rating of clinical adverse experiences
were determined.
Blood biochemistry and hematology tests, urinalysis, and an
electrocardiogram were performed at the time of screening, prior
to
dosing, and at 24 h and at 7 days postdosing in association
with
each administration. Vital signs including body temperature
and blood
pressures were monitored just before and periodically
up to 24 h
after administration.
Analytical methods.
Concentrations of biapenem in plasma and
urine samples were quantitated by high-performance liquid
chromatography (HPLC) in accordance with previously reported methods
(9). The Shimadzu (Kyoto, Japan) HPLC system consisted of a
pump (LC-6), an autosampler (SIL-6B), and a system controller
(Chromatopac C-R6A) together with a UV detector (SPD-6AV; wavelengths
of 300 and 310 nm for plasma and urine samples, respectively). An
octyldecylsilane (ODS) analytical column (TSK gel ODS 80TM [Tosoh,
Tokyo, Japan]; 4.6 mm [inside diameter] by 150 mm) was used. The
mobile phases were a mixture of 0.1 M acetate buffer and acetonitrile
(98.5:1.5, vol/vol) and a mixture of sodium 1-octanesulfate solution,
acetonitrile, methanol, and acetic acid (480:110:12:3, vol/vol/vol/vol)
for plasma and urine samples, respectively. 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 rates
were 1.2 and 1.1 ml/min for plasma and urine samples,
respectively.
Plasma samples were diluted with 30% ammonium sulfate
solution and
centrifuged at 3000 rpm. As internal standards,
5-hydroxyindole-3-acetic
acid and
o-nitroacetanilide were
used for plasma and urine samples,
respectively. For plasma, the
calibration curve was generated
by measuring the plasma solution with
the biapenem concentrations
adjusted to 2.0, 4.9, 9.9, 19.7, 49.3, and
98.5 µg/ml. The calibration
curve thus obtained was linear in this
concentration range (
r = 0.9998). Its coefficient of
variation (CV) was 1.38%. The mean
recovery (
n = 6) of
biapenem was 99.5%. The detection limit was
0.1 µg/ml in plasma. For
urine, the calibration curve was generated
by measuring the urine
solution with the biapenem concentrations
adjusted to 20.0, 50.1, 100.2, 200.4, 501.0, and 1,002.0 µg/ml.
The calibration curve thus
obtained was linear in this concentration
range (
r = 0.9999). The CV was 2.44%. The mean recovery (
n = 6)
of biapenem was 102.5%. The detection limit was 1.0 µg/ml in urine.
Pharmacokinetic analysis.
In the phase I studies using
younger healthy subjects (9), concentrations of biapenem in
plasma were fitted well to a two-compartment open model. For
comparison, the time-sequential concentrations of drug in plasma for
each subject were individually fitted to this model by employing the
nonlinear least-squares computer program (MULTI) (17). The
data apparently fitted better to a two-compartment model than to a
one-compartment model with a lower Akaike's information criterion
value. The area under the plasma concentration-time curve from 0 h
to infinity (AUC0-
) was calculated by use of the
trapezoidal rule until the time of the last quantifiable plasma
concentration and then to infinity by using the quotient of the last
measurable concentration to the terminal-phase rate constant, which was
calculated by the above-mentioned curve fitting. The steady-state
volume of distribution (Vss) was calculated by using the distribution volume of central compartment
(Vc) and two intercompartmental microconstants
(k12 and k21) as follows (11): Vss = Vc × [1 + (k12/k21)]. The maximum
concentration in plasma (Cmax) was obtained from
the simulated value at 1 h. Renal clearance (CLR) was
calculated by dividing the amount of drug excreted into the urine by
the AUC. Creatinine clearance (CLCR) was determined by
dividing the amount of creatinine excreted into the urine in the
12 h prior to drug administration by the creatinine concentration
in serum.
Statistics.
Means of the pharmacokinetic parameters were
compared among the three age groups by analysis of variance, followed
by Scheffe's multiple comparison test.
| |
RESULTS |
Clinical results.
Biapenem was well tolerated by the subjects
of all three groups. No adverse clinical effects were noted, and none
of the subjects developed any laboratory abnormalities definitely
attributable to the test drug.
Pharmacokinetic results.
Among the three age groups, there was
no significant difference in body weight (Table
1). Figures
1 and 2
illustrate the profiles of the biapenem concentration in plasma and of
the recovery of unchanged drug from urine, respectively, as a function
of time following intravenous administrations of 300 and 600 mg, the
clinically expected doses in the elderly. The pharmacokinetic
parameters are also shown in Table 1. When the three age groups were
examined, statistically significant age-related effects were found for
AUC0- total clearance (CLT), and
CLR, while the elimination half-life (t1/2) remained unchanged. Recovery of
unchanged drug from urine, expressed as percentages of 300- and 600-mg
doses, also remained unaltered: group A, 52.6% ± 3.0% (300 mg) and
53.1% ± 5.1% (600 mg); group B, 46.7% ± 7.4% and 53.0% ± 4.8%;
and group C, 50.1% ± 5.2% and 47.1% ± 7.6%. A significant linear
correlation was observed between CLR of biapenem and
CLCR at the dose of 300 mg (Fig.
3; Y = 0.782 + 0.0645X, r = 0.566, n = 15, P < 0.05) but not at the dose of 600 mg. The value of
Vss tended to be decreased with age, although
not significantly.
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FIG. 1.
Time profile of plasma concentration of biapenem (L-627)
after single intravenous administrations of 300 (A) and 600 (B) mg over
1 h in three age groups. Each symbol and error bar represents the
mean ± SD. Symbols: circles, group A; triangles, group B;
squares, group C (n = 5 for each group).
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FIG. 2.
Cumulative recovery of biapenem from urine expressed as
percentage of the dose, either 300 (A) or 600 (B) mg in three age
groups. Each symbol and error bar represents the mean ± SD.
Symbols: circles, group A; triangles, group B; squares, group C
(n = 5 for each group).
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FIG. 3.
Relationship between CLT of biapenem and
CLCR. A significant, positive linear correlation between
CLR of biapenem and CLCR was observed at the
dose of 300 mg (symbols:  , group A;  , group B;  , group C;
n = 5 for each group) (straight line, r = 0.556 [n = 15], P < 0.05). At the
dose of 600 mg, no significant correlation was observed (symbols:  ,
group A;  , group B;  , group C).
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| |
DISCUSSION |
The data from the present study revealed that a new parenteral
carbapenem, biapenem, was well tolerated in regimens using clinical
doses relevant for all ages and possessed the following different
pharmacokinetic properties in elderly subjects as compared with those
in younger subjects. Biapenem showed statistically significant
age-related effects in AUC, CLT, and CLR
values, while it showed linear pharmacokinetics in both age groups and
the t1/2 and percent cumulative recovery of
unchanged drug from urine remained unchanged.
It is well recognized that subject age affects the disposition of many
drugs because of physiological changes associated with aging. Organ
functions in the elderly generally decline as a result of advancing
age. For example, cardiac output decreases by 30 to 40% between the
ages of 25 and 65 years and the glomerular filtration rate as expressed
by CLCR declines progressively with age. Body composition
also changes with aging. Total body water and lean body mass are lower
in the elderly, both in absolute terms and as percentages of body
weight. There is an age-related increase in adipose tissue as a
fraction of body weight of 9 to 49% with a concomitant reduction in
lean body mass and body water (5). The decrease in the
proportion of lean body mass per unit of body weight has been shown to
alter the distribution volumes of various drugs (4). In
accordance with the above-mentioned observations, such age-related
alterations in pharmacokinetics as increases in
t1/2 and in concentration of drug in plasma are encountered for various types of antimicrobial agents. In fact, we
have reported age-related changes in the pharmacokinetic properties of
two fluoroquinolones, balofloxacin and grepafloxacin, whose main
excretion routes are the renal and hepatic routes, respectively
(7): delayed and diminished recovery of balofloxacin from
urine, attributed to the reduced renal function of the elderly subjects, and increases in Cmax and AUC of
grepafloxacin, attributed to a decrease in Vss
in the elderly.
In the present study, a significant linear correlation was observed
between the CLR of biapenem and CLCR, although
only at the dose of 300 mg, and Vss tended to be
decreased with age, although not significantly. CLCR was
calculated on the basis of urine collection for 12 h during the
night instead of over a whole day (24 h). Therefore, the intra- and
interindividual variabilities in urine volume during the night might
have had a relatively large influence on the accuracy of calculating
CLCR and, further, on the result that a significant linear
correlation between CLR of biapenem and CLCR
was present and absent at the doses of 300 and 600 mg, respectively. At
the dose of 600 mg, on the other hand, the elderly subjects showed
significantly lower values of CLCR (68.5 ± 8.5 and
64.8 ± 10.0 ml/min for groups B and C, respectively) than the
younger ones (89.2 ± 13.1 ml/min for group A) before drug administration (group A versus group B, P < 0.01;
group A versus group C, P < 0.01). In light of these
observations together with the above-mentioned physiological changes in
relation to aging, the age-related decreases in AUC, CLT,
and CLR of biapenem could be attributed to the combination
of decreased lean body mass and lowered renal function in the elderly
subjects. Since t1/2 and percent cumulative
recovery of unchanged drug from urine, however, remained unaltered, it
is not expected that the accumulation of biapenem would result when
administered at 8- to 12-h intervals, in other words, two or three
times daily.
When a -lactam antibiotic is prescribed for an elderly patient,
precautions should be taken with regard to age-related changes in
pharmacokinetic properties. However, in consideration of the safety and
tolerance profiles of -lactam antibiotics including carbapenem, the
magnitude of age-related changes observed in the pharmacokinetics of
biapenem does not necessitate dosage adjustment in elderly patients
with renal function normal for their age.
| |
ACKNOWLEDGMENT |
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science and Culture in 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, June 1998, p. 1433-1436, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
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Nagashima, S., Kozawa, O., Otsuka, T., Kohno, K.-i., Minamoto, M., Yokokawa, M., Kanamaru, M., Uematsu, T.
(2000). Pharmacokinetics of a parenteral carbapenem, biapenem, in patients with end-stage renal disease and influence of haemodialysis. J Antimicrob Chemother
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Abstract
Introduction
