ANTI-INFECTIVE
AGENTS
Disposition of Cefpodoxirne Proxetil in Hemodialysis Patients T. Bonn,
Marie
Bruce
PhD,
E. Shapiro,
George
MD,
S. Hughes,
and
Charles
MD,
FCP,
Judy
S. Kelloway,
E. Halstenson,
PharmD,
PharmD,
FCP
The disposition of cefpodoxime after single, oral 200-mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open-label study of six patients with end-stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half-life for the interdialytic period was 18.0 ± 6.5 hours; apparent total body clearance was 28.6 ± 13 mL/minute. The half-life during hemodialysis, 2.66 ± 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 ± 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 ± 31 mL/minute, which was 57.1 ± 13% arid 71.7 ± 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 ± 0.25 hour hemodialysis session removed 22.4 ± 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 ± 0.33 mcg/mL was observed, at about one-half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted. The recommended dosing interval for cefpodoxime proxetil in patients with end-stage renal disease is three times a week, after hemodialysis.
C efpodoxime
proxetil (U-76252), an orally active cephalosporin antibiotic, is a prodrug that is deesterified in vivo to its biologically active metabolite, cefpodoxime (U-76253), which has in vitro activity against many common gram-positive and gram-negative bacteria. Conversion of the orally administered prodrug to active cefpodoxime is believed to be mediated by nonspecific intestinal brush border esterases.1’2 Cefpodoxime exerts its antibacterial activity by binding to penicillin-binding proteins, thereby causing abnormal bacterial wall synthesis and lysis.’ Clinical studies have shown the efficacy of cefpodoxime proxetil for treatment of urinary tract infec-
tions, gonorrhea, and upper and The disposition
structure infections, tract infections.413 proxetil has been studied in patients with mild to severe renal impairment.14’15 The results of these studies indicated that cefpodoxime half-life in patients with moderate and severe that
Minnesota. Address for reprints: pany, 7215-24-2, 301 Henrietta
1fl20
-
i
flht
flLI
Marie T. Bonn, PhD, The Upjohn ComStreet, Kalamazoo, Ml 49007.
lflflfl.’fl.1fl’O
dysfunction volunteers,
was prolonged and apparent
relative
to
total body clearance and renal clearance declined as renal function diminished. Dosage adjustment in patients with creatinine clearance less than 50 mL/min was in
recommended. Hemodialysis
stage From the Clinical Pharmacokinetics Unit (Dr. Bonn) and the Clinical Research Unit (Dr. Hughes), The Upjohn Company, Kalamazoo, Michigan; The Drug Evaluation Unit, Hennepin County Medical Center (Drs. Kelloway, Shapiro, and Halstenson) and the College of Pharmacy, University of Minnesota (Drs. Kelloway and Halstenson), Minneapolis,
renal normal
skin and skin lower respiratory of cefpodoxime
mented
renal three
is warranted
failure. times
This
in
patients
procedure
a week,
and
the
with
end-
is typically
imple-
duration
of each
dialysis is about 3 hours. Hoffler et al.16 investigated the pharmacokinetics of cefpodoxime pro xetil in patients with end-stage renal disease undergoing hemodialysis. A parallel design was used with respect to interdialytic and intradialytic treatment groups. Serum cefpodoxime concentrations in hemodialysis
DISPOSITION
OF
CEFPODOXIME
PROXETIL
IN
ing the fasting patients were much higher than in healthy volunteers, and cefpodoxime was dialyzable. Based on these findings, a modified dosage schedule was recommended for hemodialysis patients. The current study was conducted to further evaluate the effect of end-stage renal disease on the disposition of cefpodoxime after a single, oral 200-mg dose of cefpodoxime proxetil (cefpodoxime equivalents) using a crossover design with respect to interdialytic and intradialytic periods. Thus, the same subjects were dosed on an off-dialysis day and a few hours before hemodialysis to obtain reliable estimates of the dialytic clearance rate and the extent to which cefpodoxime is dialyzed. MATERIALS
AND
METHODS
Subjects Six adult volunteers enrolled in the study after giving written informed consent. Subjects participated in the study after giving a medical history and undergoing a physical examination, an electrocardiogram, and clinical laboratory tests. Subjects who had received known enzyme-inducing agents, theophylline, cimetidine, metoclopramide, or similar drugs within 30 days or antibiotics within 10 days of study initiation were excluded. No caffeine or caffeinecontaining substances were allowed for 48 hours before or throughout the study. All subjects refrained from alcohol 1 day before and until study completion. Concurrent drug therapy considered necessary for the volunteer’s welfare was permitted. This included drugs associated with dialysis and drugs for the treatment of anemia, chronic cardiovascular disorders, gastrointestinal discomfort, allergies, pain, insomnia, and hypoparathyroidism. Diet supplements and aids for smoking cessation also were allowed. Aluminum hydroxide-containing antacids, Shohl’s solution, or calcium supplements were not taken 4 hours before or for 4 hours after dosing. Drug
Administration
Subjects took single, oral 200-mg doses of cefpodoxime proxetil (dose expressed in cefpodoxime equivalents) on two occasions separated by at least 2 weeks. Subjects were randomized to one of two treatment groups, which differed in the sequence of being treated between periods of dialysis (interdialytic period) or during dialysis (intradialytic period). Each subject took two cefpodoxime proxetil 100-mg tablets (Lot #25,267, The Upjohn Co., Kalamazoo, MI) orally with 6 ounces of water after an overnight fast. Fasting was continued for 4 hours after dosing. Dur-
*p.rri
IMrI”rIt,r
A,’rRrro
water
was
Sample
HEMODIALYSIS
period,
no food
or beverage
other
than
allowed.
Collection
Blood samples (7 mL) were collected in lavendertopped tubes (Becton-Dickinson, Rutherford, New Jersey) containing freeze-dried ethylenediaminetetra-acetic acid as anticoagulant. During the interdialytic and intradialytic phases, samples were obtained immediately before dosing (0 hour) and at the following times after dosing: 0.33, 0.67, 1, 1.5, 2, 2.5, and 3 hours. Additional blood samples were collected at 4, 6, 8, 10, 12, 16, 20, 24, 36, and 48 hours after dosing in the interdialytic period. Hemodialysis with a single-pass dialysis machine was scheduled to begin approximately 3 hours after drug administration, and arterial (predialysis filter) and venous (postdialysis filter) blood was collected at 0.5, 1, 2, and 3 (or end of dialysis) hours after the start of dialysis. Venous blood only then was obtained at the following times relative to the end of dialysis: 0.17,0.33, 0.50, 0.75, 1, 2, 4, 6, 10, 14, 18, 30, and 42 hours. Plasma was harvested from each specimen, frozen on dry ice, and stored at -20#{176}Cuntil assayed. Urine was collected from all subjects who were not anuric before dosing (-12 to 0 hour) and for 48 hours after dosing in the following intervals: 0 to 6, 6 to 12, 12 to 24, 24 to 36, and 36 to 48 hours. During each collection period, the urine flask was stored at 4#{176}C. Urine volumes were quantitated, and an aliquot was saved and frozen at -20#{176}Cuntil analysis. During the intradialytic period, a dialysate sample was collected before the start of hemodialysis and then at the following intervals: 0 to 0.5, 0.5 to 1, 1 to 1.5, 1.5 to 2, 2 to 2.5, 2.5 to 3, and 3 hours to end of dialysis. Dialysate volumes were recorded and an aliquot of each collection was stored at -20#{176}Cuntil assayed. Analytical
Procedure
Concentrations of cefpodoxime in plasma, urine, and dialysate samples were determined by a microbiologic method.17 Quantitation of cefpodoxime was based on the diffusion of 30-1iL samples from 6-mm wells into Antibiotic Medium #1 (Difco) seeded with 0.15% (vol/vol) Providencia rettgeri, UC-12186 (CDC #4334-69, Bronson Methodist Hospital, Kalamazoo, MI). Zones of inhibition were measured and read against the standard curve. The assay was linear over the cefpodoxime concentration range of 0.05 to 1.28 ig/mL and showed a mean recovery of 94%, maximum within-run precision of 3.9%, and between-run precision of 8.0%. Samples with drug 1ev-
I 11fl
BORIN
ET
els greater than 1.28 g/mL were diluted with either pooled plasma or phosphate-buffered saline to obtain a linear standard curve. Specificity of this microbiologic method for cefpodoxime has been demonstrated previously in studies comparing high-pressure liquid chromatography and microbiologic assay results; excellent correlations between the two methods were observed for cefpodoxime levels in plasma and in urine, with close agreement between assay concentrations.18 Additionally, cefpodoxime undergoes minimal biotransformation in humans,19 which greatly reduces the potential for assay bias due to active metabolites. Pharmacokinetic
Analysis
Pharmacokinetic parameters were calculated using noncompartmental methods. Terminal elimination rate constants (k0J were estimated by least squares regression of log-transformed cefpodoxime plasma concentration-time data in the terminal linear phase. For the interdialytic period, regressions were carried out using the 12- to 48-hour post-dose samples. The terminal elimination half-life (t#{189}) was calculated as 0.693/k01. Plasma cefpodoxime area under the concentration-time curve from time 0 to infinity (AUC) was estimated using the trapezoidal rule for time 0 to the last measured plasma concentration and then extrapolating to infinity by adding the last measured plasma concentration divided by k01. Apparent cefpodoxime total body clearance (CL,jF) was calculated as the dose divided by AUC0. The absorption rate constant (k0) was determined using the Wagner-Nelson method. The lag time to beginning of absorption (tiag) was estimated by nonlinear regression analysis of the fraction absorbed (fa) versus time data fitted to the following relationship:
TABLE Subject Subject
No.
Sex
Demographic
Race
1040
Black,
S
-
RESULTS Subjects participating in the study ranged in age from 37 to 66 years (mean, 50.7 years) and in weight from 50.0 to 106 kg (mean, 74.7 kg). Individual subject demographics are listed in Table I. Mean plasma cefpodoxime concentration-versustime data are shown in Figure la and lb. Individual subject pharmacokinetic parameters for the interdialytic period are summarized in Table II, and intradialytic parameters are displayed in Table III. Pharmacokinetic parameters for the posthemodialysis period appear in Table IV. The time that patients were on hemodialysis ranged from 2.5 to 3.1 hours (Table V).
I Characteristics Age (yr)
Weight
(kg)
Height
(cm)
M M M
B C C
41 45 56
70.5 74.1 106
175 180 188
4
F M F
A C C
59 37 66
81.8 65.5 50.0
50.7 11.4
74.7 18.7
160 173 168 174
Mean SD =
= I e -t-t The apparent volume of distribution (Vd/F) was determined as CL/k01. The maximum plasma concentration of cefpodoxime (Cmax) and the time to achieve maximum concentration (tmax) were estimated by visual inspection of individual concentration-time profiles. Urinary excretion of cefpodoxime was determined by multiplying urine concentrations by the corresponding urine volume values. The amount of drug recovered in the dialysate (AD) was similarly calculated. Renal clearance of cefpodoxime (CLPJ was calculated as Ae8/AUC0, where Ae is the amount of cefpodoxime recovered in the urine from time 0 to time 48 hours and AUC is the area under the plasma concentration-versus-time curve during the same time interval. Dialysis clearance (CL) was determined as AD/AUCHD where AUCHD is the area under the prefilter plasma concentration-time curve during hemodialysis. Dialyzer creatinine (CLCPJ and urea nitrogen (CLBUN) clearances were similarly calculated.
1 2 3
5 6
B
AL
C
=
Caucasian,
J Clin Pharmacol
A
=
Native
American.
1992;32:1038-1044
9.7
DISPOSITION
OF’ CEFPODOXIME
PROXETIL
IN
HEMODIALYSIS
a IT
-J
)(
??9o
i
1001
0’
OU
110
0I
j
10
1.000 o2 Et 00 .2#{176}
1
0
0.100 10
20 Time
40
30
50
(hours)
20
Time
Figure
1. Mean
intradialytic
During
plasma period.
cefpodoxime
hemodialysis,
considerably
shorter
concentration-time
half-life
cefpodoxime than
in
the
profiles
interdialytic
for six subjects
was
and CL0 was much higher, indicating efficient removal of the drug during hemodialysis. Cefpodoxime CLHD was 71.7 ± 25% and 57.1 ± 13% of the hemodialysis clearance for creatinine and urea nitrogen, respectively. These values represent the approximate rate at which cefpodoxime is cleared by the dialyzer relative to creatinine and urea nitrogen removal. The amount of drug recovered in the dialysate was 22.4 ± 2.9% of the administered dose. After cessation of hemodialysis, the maximum increase in cefpodoxime plasma concentration ranged from 8.8% to 77% and occurred at approximately 30 minutes in 5 of the 6 subjects. Rebound parameters could
TABLE Interdialytic
Cefpodoxime
Pharmacokinetic
Parameters
(a) during
not be estimated sis
period
dosed
arterial
half-life hours, during
after which the
an interdialytic
in one
sample
(hours)
subject
was
not the
period
an
a post-dialyCefpodoxime
averaged to
interdialytic
or (b) during
because collected.
hemodialysis is similar
period,
19.2
mean
value
(18.0
± 6.5
± observed
3.5
hours).
DISCUSSION Cefpodoxime
is a cephalosporin
that
has
low
by renal excretion.19 It has been demonthat the elimination of cefpodoxime is deon renal function.15 The results of the study in patients with end-stage renal dis-
are
consistent
with
to 23%)
is eliminated
primarily
ease
(18
and
protein
strated pendent current
binding
agent
plasma
this
finding.
Cefpodoxime
II After
a Single
200-mg
Dose of Cefpodoxlme
Proxetil
Subje ct No. Parameter
Cmax
1
(mcg/mL)
tmax(hr) tuag(hr)
ka (hr’) k01, (hn) (hr) AUC(mcg-hr/mL) CL/F(mL/min) t’/2
Fe(%) CLR (mL/min)
Vd/F
(L/kg)
ANTI-INFECTIVE
AGENTS
2
3
4
5
6
Mean
4.13 4.00
3.53 8.00
6.32 6.05
5.94 6.05
4.76 5.02
5.18
3.45
2.00
4.00
0.41 1.66 0.052
0.30
0.57
0.691 0.062
0.775 0.032
13.4 107 31.1
11.3 68.6
21.9 136
48.6
24.6
8.54 2.89 0.498
2.03 1.05 0.639
0.00
0.36
0.05
SD
1.24 2.11 0.22
0.28
0.363
0.539
0.783
0.80
0.049
0.024 28.5
0.037 18.6 176
0.043 18.0 140
19.0
14.0
Anunic
92.8 35.9 0.42
263 12.7 Anuric
2.10
28.6 3.27
1.14 0.439
0.17 0.516
Anuric 0.479
0.49 0.611
1.15 0.530
1
0.449 0.014 6.47 70.4 12.8
3.60 1.05 0.078
1041
TABLE Intradlalytic
Cefpodoxime
Pharmacokinetic
Parameters
III After
Subject
a Single
200-mg
Dose of Cefpodoxlme
Proxetil
No.
Parameter
1
2
3
4
5
6
Mean
SD
Cmax (mcg/mL) tmax (hr) k51-HD (hr’) t1/2-HD (hr) AUC(mcg.hr/mL) CLHD(mL/min)
3.37
3.28
3.87
2.00
2.50
3.00
2.71 3.00
0.248
0.429
0.243
4.95 2.00 0.183 3.79 8.25 109 1.12
3.51 2.58 0.280 2.66 6.10 120 1.10
0.82 0.49 0.086 0.74 1.27 30.8 0.67
0.328
2.12 5.61
F5 (%) CLR (mL/min) A(mg) AD (% of dose)
2.79 6.83
126
112
1.99
0.89 1.05 46.0 23.0
1.86
42.3 21.1
1.62 5.96 70.9 Anunic
2.85 5.20 142 0.39
2.85 3.00 0.250 2.78 4.75 161 Anuric
Anuric
0.32
Anunic
0.52
0.94
0.69
44.2 22.1
45.8 22.9
54.1 27.1
44.7 22.4
5.88 2.94
36.0 18.0
elimination half-life in hemodialysis patients (18.0 ± 6.5 hours) was much higher than that reported in patients with severe renal impairment (9.8 ± 1.2 hours).15 The AUC,D was higher and CL/F was lower in hemodialysis patients than in subjects with severe renal impairment. Apparent volume of distribution was similar to previous estimates in normal volunteers (0.70 L/kg) and subjects with mild to severe renal impairment (0.57 to 0.80 L/kg),15 which is consistent with the low protein binding of cefpodoxime. Patients with end-stage renal disease on an interdialytic day had a higher Cmax and prolonged tmax relative to healthy volunteers and patients with mild to severe renal impairment. The tieg and k5 estimates were comparable among all subject groups.
The absolute bioavailability of cefpodoxime proxetil is about 5#{216}%20 Although the apparent increase in Cmax and tmax for patients with end-stage renal disease relative to healthy volunteers and patients with mild to severe renal dysfunction may be due to increased drug absorption, it is more likely to be related to a reduction in elimination of cefpodoxime, because Vd/F was unchanged. In those hemodialysis patients who were able to produce urine, urinary excretion and renal clearance of cefpodoxime were much lower than in patients with less impairment of renal function, as expected for a compound that is cleared primarily by renal mechanisms. The results of this study are in agreement with the findings reported previously for hemodialysis patients dosed either off dialysis or during dialysis.16
TABLE Post-Hemodialysis
Period
Pharmacokinetic Subject
Parameter
Maximum change Cp8 (mcg/mL) Percent tmax(hr) k, (hr’) t1/2 (hr) * Cp t ND
1042
increase
=
5
Parameters
No.
1
2
3
4
5
6
Mean
SD
0.68 77.3
0.25 19.7
NDt ND
0.14 11.6
0.15 8.77
0.85 42.5 0.75 0.040 17.1
0.41 32.0 0.52 0.037 19.2
0.33 28.6 0.23 0.007 3.52
in in Cp
0.50
=
IV
ND
0.68
0.50
0.049
0.032
24.3
14.2
21.5
0.035 19.8
0.038 18.3
plasma cefpodoxime concentration. not determined; post-dialysis arterial
J CIin Pharmacol
0.17
0.029
sample
1992;32:1038-1044
not drawn.
TABLE Hemodlalysis*
V Parameters
Subject Parameter
1
2
3
4
5
6
3.00
3.08
2.97
3.02
2.50
2.58
Mean
SD
Time on dialysis (hr)
Dialysate rate
Plasma rate Dialyzer
0.25
(mL/min)
704
499
506
487
517
543
543
81
flow (mI/mm)
250
291
217
304
279
295
273
33
176
220
205
225
240
196
210
22.8
114
167
192
194
191
188
174
31.2
CLBUN
(mI/mm) Dialyzer CLCR (mL/min) *
2.86
flow
Travenol
CA2I 0 dia!yz er filter
used for a II subjects.
The disposition of cefpodoxime proxetil in patients with end-stage renal disease is similar to that of other oral cephalosporin agents, such as cefprozil, cefetamet pivoxil, and cefotiam hexetil.223 Cefpodoxime is dialyzable to a greater extent than cefixime but less than cefprozil during a 3-hour hemodialysis procedure.21’24 Because Vd/F is unchanged in patients with endstage renal disease maintained on hemodialysis, the dose of cefpodoxime proxetil need not be altered from that in patients with normal renal function. To avoid accumulation of drug, the frequency of dosing
should be reduced. Cefpodoxime plasma concentrations were simulated with the super-position principle using mean data from the intradialytic and interdialytic periods and a dosing schedule in which patients receive a 200-mg dose of cefpodoxime proxetil three times a week after dialysis (Figure 2). This regimen provides a mean peak concentration of 4.9 sg/ mL and trough levels exceeding 0.37 zg/mL, which are above the M1C90 for most organisms in cefpodoxime’s antibacterial spectrum. In summary, the disposition of cefpodoxime proxetil is altered in the presence of end-stage renal disease. Hemodialysis removed about 22% of the administered dose. Because of the prolonged elimination half-life of cefpodoxime but an unchanged Vd/F in hemodialysis patients, dosage adjustment is not required, but extension of the dosing interval is warranted. It is recommended that cefpodoxime proxetil be administered three times a week after hemodialysis to provide trough concentrations exceeding 0.37 ig/mL for a 200-mg dose.
The authors thank the Drug Evaluation tance.
the staff of the Clinical Unit and Sheila O’Meara
Research Section of for secretarial assis-
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Figure 2. Simulated files after niultiple administered three
ANTI-INFECTIVE
plasma cefpodoxime concentration-time oral doses of 200 mg of cefpodoxime times a week after hemodialysis.
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