ANTI-INFECTIVE
Pharmacokinetic Cefpodoxime Dose Marie
and Tolerance after Singleand Oral Administration Cefpodoxime Proxetil
T. Bonn,
PhD, Max
George
S. Hughes,
MD,
E. foyer,
MS, and
K. Sue
Cefpodoxime proxetil, a third generation, ministered in single doses of 100, 200, 400, ime equivalents) and multiple doses of 100, teers. The pharmacokinetics of the active
FCP,
metabolite,
Rajendra
Cathcart,
broad-spectrum, 800
600, and 200, and
Studies Multipleof
oral
cefpodoxime,
BS,
BS was
cephalosporin,
mg (dose expressed
400 mg twice
K. Patel,
of
ad-
as cefpodox-
daily to healthy and tolerance
volun-
of cef-
podoxime cefpodoxime
proxetil were determined. Results from the single-dose study indicate that exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.
C
efpodoxime proxetil is a third generation, broadspectrum cephalosponin for oral use. It is a prodrug that is believed to be de-esterified in the intestinal epithelium by nonspecific esterases to yield its active metabolite, cefpodoxime.1’2 Cefpodoxime acts by binding to penicillin-binding proteins, thus interfering with bacterial cell wall synthesis.3 Its antibacterial spectrum includes staphylococci, streptococci, and gram-negative species (Citrobacter, Hemophilus, Klebsiella and Proteus spp). Cefpodoxime is not active against most anaerobes, Pseudomonas species, methicillin-resistant Staphylococcus, on Enterococcus.2’4
From mazoo,
the
Clinical
Michigan.
Pharmacokinetics
Pharmacokinetics
Unit,
Upjohn
Company,
for reprints:
Marie 1. Bonn,
(7215-24-2),
The
Company,
Upjohn
49007.
J ClIn Pharmacol
The
Address
1991;31:1137-1
145
Kala-
PhD. Clinical Kalamazoo,
Ml
Pharmacokinetic studies of cefpodoxime in humans after oral administration of single 200-mg doses of cefpodoxime pnoxetil have shown that the drug is rapidly absorbed (absorption half-life of approximately 1 hr) and has a terminal disposition half-life of approximately 2.1 hours.5 Approximately 37% of the administered dose of cefpodoxime proxetil is excreted renally as cefpodoxime.5 The current study evaluated the pharmacokinetics, dose proportionality, and tolerance of cefpodoxime proxetil after singleand multiple-dose oral administration
of cefpodoxime
proxetil
to normal
vol-
unteers. Plasma samples that were collected in this study were assayed for cefpodoxime concentration by both microbiologic and high-pressure liquid chromatography (HPLC) methods, and the resulting assay concentrations and pharmacokinetic parameters were compared to determine how closely the microbiologic assay results agreed with those from the specific HPLC method.
1137
BORIN
800 mg (n = 7). In the multiple-dose study, 32 subjects were randomly assigned to the following treatment groups: placebo (n 8), 200 mg/day (n = 8), 400 mg/day (n = 8), or 800 mg/day (n = 8). These ran-
METHODS Subjects
=
Eighty-two
healthy
adult
volunteers
participated
in
the singleand written informed had
normal
trocardiograms, stool
multiple-dose studies after giving consents and medical histories; all results of physical examinations, elecclinical laboratory tests (including
specimens
to verify
absence
of toxin
to Clostrid-
ium difficile), and a negative surface antigen to hepatitis B, and all were drugfree as determined by a urine drug screen. Subjects did not have a history of hypersensitivity were not to
to penicillins or cephalosporins taken any other medications, for 10 days before the start
have
cluding antibiotics, study. Participants tions, other than
were not allowed the study medication,
and inof the
any medicathroughout
the
study. Subjects (33 men, 17 women) in the single-dose study ranged in age from 19 to 45 years and in body weight from 46 to 102 kg. Thirty-two male volunteers ranging in age from 24 to 51 years and in body weight from 58 to 98 kg, participated in the multipledose study. Subject demographics by treatment group are given in Table I.
Study
study, groups: 8), 400
=
50 subjects were randomplacebo (n = 11), 100 mg (n mg (n = 8), 600 mg (n = 8), or
TABLE I Subject Demographics Study! Treatment Group
domized, double-blind, were conducted according Drug
Administration
Each
subject
by Treatment Age (yr)*t
Male/Female
Single Dose Placebo 100 mg 200 mg 400 mg 600 mg 800 mg Multiple Dose Placebo 200 mg/day 400 mg/day 800 mg/day Mean ± SD. Statistically significant mg/day treatment groups.
6/5 4/4 5/3 6/2 7/1 5/2
29.9 30.0 27.7 29.3 26.6 33.4
8/0 8/0 8/0 8/0
34.1 38.6 28.3 33.5
difference
(P < .05)
± ± ± ± ± ±
Group Weight (kg)s
7.8 7.4 7.5 7.3 6.2 10.7
73.7 70.3 72.6 76.6 69.7 73.4
±
7.2 6.5 4.6 8.0
75.4 75.7 69.3 74.5
± ±
± ± ± ±
between
400
mg/day
± ± ± ± ±
± ±
13.1 15.0 15.2 12.8 15.1 9.4 11.7 9.2 7.7 10.0
and 200
Treatments
#{149} J Clin Pharmacol
1991;31:1137-1145
single-dose
were
study
administered
in the appropriate doxime proxetil
trials design.
received
either
24,832,
as film-coated
combination of placebo 100-mg tablets (Lots Kalamazoo, MI) with
Upjohn,
tablets
and cefpo24,767 and 240 mL of
water. Clinical Safety made
vated
Observations laboratory before and
and and
Laboratory
clinical
Tests
observations
were
24 hours after dosing in the singleAll safety laboratory studies were cona 12-hour fast. These included hematol-
blood count, thromboplastin
partial
prothrombin time, actitime, fibrinogen, direct
Coombs’ test), chemistry (multiple serum chemistry tests), and urinalysis. In addition, a 24-hour urine collection was done before and 24 hours after dosing.
An electrocardiogram was done with the aforementioned safety laboratory studies before dosing and again at .24 hours after dosing. Cardiac telemetry was done 24 hours before and for 24 hours after dosing. Audiometry (Bekesy audiometer, Industrial Acoustics, Bronx, NY) was done before and for 24 hours after dosing. Special laboratory tests included a template bleeding time (Simplate II, General Diagnostics, Durham, NC) which was done on the volunteer’s forearm prior to dosing, 2 hours after dosing (which was the expected peak plasma level), and again at 24 hours after dosing. Vital signs were measured before and at 2, 8, 12, 24, 36, and 48 hours after dosing. Volunteers were asked about adverse medical events at the same time vital signs were collected. The same panel of clinical tests and observations were done on volunteers in the multiple-dose study as for those in the single-dose study. All of the safety laboratory studies were collected after a 12-hour fast before and 24 hours after the first and last doses, and every 3 days while on the study. A 24-hour urine
collection
1138
in the
placebo-controlled to a parallel
placebo, or 100, 200, 400, 600, or 800 mg of cefpodoxime proxetil (dose expressed as cefpodoxime equivalents). Participants in the multiple-dose study received either placebo or 100, 200, or 400mg of cefpodoxime proxetil every 12 hours for 141/2 days.
dose study. ducted after ogy (complete
Design
In the single-dose ized to six dose 8), 200 mg (n
t
ET AL
was
done
before
and
after
the
first
and
last
PHARMACOKINETICS
doses. hours
Audiometry after the first
was performed and last doses
AND
before on day
and
TOLERANCE
and 24 7 (mid-
point of dosing regimen). Vital signs were measured on each day of the study, before dosing and twice daily thereafter. After the first and last doses of the study, vital signs were also taken at 2, 8, 12, 24, 36, and 48 hours after dosing. A template bleeding time was done as in the single-dose study on the first and last
days
of the
Specimen
study.
Collection
OF
Specimens trifuged
samples
(5 mL)
were
PROXETIL
immediately
placed
on ice and
cen-
3000 rpm for 6 minutes at 4#{176}C.The plasma was harvested, split, frozen immediately on dry ice, and stored at -70#{176}C until analysis. Urine was collected before dosing and each time the subject voided over the 48-hour period after drug
at
administration
in the
single-dose
study.
Urine
was
collected before dosing and at the following collection intervals after the first (day 1) and last (day 15) doses in the multiple-dose study: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10, and 10 to 12 hours. After each void, the
time Blood
CEFPODOXIME
of collection
and
urine
weight
were
recorded.
A
for determination of cefpodoxime concentrations were collected at 0 hour (before drug administration), and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after drug administration in the single-dose study. In the multiple-dose
5-mL aliquot dry ice bath
study, blood samples drug administration),
Concentrations of cefpodoxime in plasma and urine were determined using reversed-phase high-pressure liquid chromatography (HPLC) methods and a microbiologic assay. In the HPLC plasma procedure,
were taken at 0 hour (before and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the first dose on day I and after the last dose on day 15. Additional samples were collected on day 15 at 16, 20, and 24 hours.
Analytical
of each collection was frozen using and stored at -70#{176}C until analysis.
a
Methods
samples
were
acidified
with
12
14
16
18
a phosphoric
acid
solu-
7
6 E
5
‘a
4
3
CD
= 03
‘a =
2
C C.,
1 0
0
2
4
6
8
10
Time After Drug Administration Figure 400
1. Average mg;
.
600
ANTI-INFECTIVE
plasma cefpodoxime mg; D, 800 mg.
concentrations
after
single-dose
administration
20
22
24
(hr)
of cefpodoxime
proxetil.#{149}, 100 mg; & 200
mg:#{149},
1139
BORIN
tion that contained internal standard (7-fl-hydroxyethyltheophylline) and extracted onto C8 reversedphase cartridges using an advanced automated sample processor (AASP). The absorbed drugs were eluted directly from the cartridges onto a C18 column using a mobile phase consisting of 0.05 M sodium acetate buffer (pH 5.2) and acetonitrile in a ratio of 93:7 (vol/vol). The eluate was monitored using UV detection at 254 nm. The linear range for analysis of cefpodoxime in plasma was 0.02 to 10 mcg/mL. The between-day coefficient of variation (CV) ranged from 25% for the low standard to 1.9% for the high standard. Assay precision, expressed as the CV of estimated concentration of quality control (QC) samples, ranged from 7.0% for the low (0.1 mcg/mL) QC sample to 2.5% for the high (4.0 mcg/mL) QC sample. Recovery was 96 to 100% in plasma. Urine cefpodoxime concentrations were determined by direct injection of filtered urine samples onto a C18 guard column using a mobile phase of 0.2% phosphoric acid (pH 2.0) and methanol in a ratio
of
90:10
(vol/vol).
After
a loading
period,
the
guard column was switched into the analytical stream, and the eluent was chromatographed on a C18 column using the mobile phase described earlier in the plasma analysis. Standard curves in urine were linear over the concentration range of 0.1 to 50 mcg/mL. The betweenday CV ranged from 24% for the low standard to 5%
ET
AL
for the high standard. Assay precision ranged from 2.9% for the 1.0 mcg/mL QC sample to 4.5% for the 24.5 mcg/mL QC sample. Recovery was 100 to 103% in urine. Quantitation of cefpodoxime in plasma was determined using a previously described microbiologic assay with Providencia rettgeri as the test organism.5’6
Linearity
was
established
over
the
cefpodox-
ime concentration range of 0.04 to 1.28 mcg/mL. Plasma samples were diluted with pooled plasma, as necessary, to obtain a linear standard curve. The assay showed a mean recovery of 94% and a maximum within-run precision (CV) of 3.9% and a betweenday CV of 8.0%. Pharmacokinetic
Analysis
Cefpodoxime pharmacokinetic parameters were determined by noncompartmental methods.7 Elimination rate constants (Xj were estimated by leastsquares regression of plasma cefpodoxime concentration-time data points lying in the terminal log-linear region of the curves. Elimination half-life (t112) was calculated as 0.693/X. Areas under the plasma concentration-time curve (AUC) and under the first moment curve (AUMC) were calculated by the trapezoidal rule. AUC and AUMC from time zero to infinity were obtained by adding extrapolated areas (AUCT_ and AUMCT_cc,, respectively) to AUC and AUMC determined from time zero to the time of
TABLE II Average
(SD) Cefpodoxlme Pharmacokinetic Parameters After Single-Dose Oral Administration of Cefpodoxlme Proxetil Dose
Parameter
AUC (mcg. hr/mL) Dose-normalized AUC (mcg.hr/mL) CIA/F (mL/min) Cmax (mcg/mL) Dose-normalized
mg
100
7.38
.1 ClIn
400
mg
(2.85)
13.1 (3.64)
22.7
7.38(2.85) 249 (71.2) 1.45 (0.46)
6.56(1.82) 268 (61.9) 2.34 (0.76)
5.67(1.23) 305 (58.2) 3.72 (0.97)
1.45 (0.46) 2.0 (0.67) 4.12 (0.61) 0.33 1 (0.074) 2.1 39.5 (4.9) 97.6 (30.1)
* Dose expressed as cefpodoxime equivalents; except n = 7 for 800-mg dose group.
S
mg
(4.90)
600 mg
35.8
(6.04)
5.96(1.01) 288 (55.7) 5.31 (1.20)
800 mg
44.3
(7.55)
5.54(0.95) 309 (54.2) 6.61 (1.64)
Cmax
(mcg/mL) Tmax (hr) MRT (hr) X2 (hr) Half-life (hr)t F (%) Cir (mL/min)
1140
200
*
Pharmacol
1991;31:1137-1
n
=
1.17 2.3 4.76 0.283
(0.38) (0.46) (0.69) (0.082) 2.5 32.3 (6.5) 84.4 (17.4)
8 subje cts per dose group,
145
0.93 2.6 5.31 0.244
(0.24) (0.82) (0.85) (0.035) 2.8 32.3 (5.3) 96.0 (10.6)
Harmonic
mean.
0.89 3.3 5.71 0.252
(0.20) (1.3) (1.03) (0.066) 2.8 30.0 (5.0) 84.7 (13.3)
0.83 2.9 5.68 0.220
(0.21) (0.69) (0.78) (0.025) 3.2 26.8 (4.6) 81.2 (9.89)
PHARMACOKINETICS
AND
TOLERANCE
the last detectable sample concentration, T, or 12 hours for the first dosing interval in the multipledose study. Peak-plasma concentration (Cmax) and time-to-peak concentration (Tmax) were determined by inspection of individual subject concentration-time curves. Dose-normalized AUC and Cmax were estimated by normalizing values to the 100-mg dose. Mean residence time (MRT) was calculated as AUMC/AUC. Apparent systemic clearance (Cl,/F) was estimated as dose/AUC. Drug accumulation in plasma after multiple dosing was calculated by dividing AUC at steady state by AUC for the first dosing interval (0-12 hr).8 Urinary excretion of cefpodoxime was determined by multiplying urine concentrations by the corresponding urine volumes. Cumulative urinary excretion (Ae) was calculated by summing the amounts of drug excreted at each of the collection intervals. Fe, the fraction of the administered dose excreted in the urine, was determined as Ae divided by the dose. Estimation of renal clearance (Clr) is given by A0 /AUC.
Cefpodoxime from
the
plasma
single-dose
study
concentration-time were
fitted
data to a one-com-
partment or two-compartment pharmacokinetic model with first-order absorption and elimination using RSTRIP.9 Weighting functions of 1, 1/C1, and 1/C12 were used, where C1 is the plasma concentration at time t. Goodness of fit for the different weights and models was determined by visual examination and by comparison of values for the model selection criteria
(MSC),
as defined
by
Fox.9
Differences in cefpodoxime pharmacokinetic parameters among dosing groups were investigated using a one-way analysis of variance (ANOVA) model. When the P-value for the ANOVA was statistically significant (P < .05), the LSD procedure was used for pairwise comparison of treatment means. A paired t-test procedure was used to determine the statistical significance of pharmacokinetic parameter differences between analogous first-dose and last-dose (steady-state) data within treatment groups in the multiple-dose study. Correlations between microbiologic and HPLC plasma assay results were examined using
simple
least-squares
regression
analysis.
RESULTS Single-Dose
PROXETIL
cokinetic parameters and dose-normalized Cmax showed statistically significant among treatments for Cmax, Tmax, X Dose-normalized Cmax was significantly the 400-, 600-, and 800-mg doses than for dose. This same trend was observed with malized AUC (AUG values after the 400-, 800-mg
doses
were
23-25%
100-mg dose), but these cally significant. Tmax significantly
higher
lower
than
differences after the
than
that
AUC and differences and MRT. lower after the 100-mg dose-nor600-, and
that
after
the
were not statisti600-mg dose was
after
the
100-
or 200-
mg dose. MRT also increased with dose, as evidenced by statistically significant differences in pairwise comparisons between the low (100- and 200-mg) and high (400-, 600-, and 800-mg) doses. The half-life of cefpodoxime appeared to increase with dose. However, only differences in X between the 100-mg and 400-,
600-,
cant.
F0 was
or 800-mg doses were statistically signifi18 to 32% lower after the 200-, 400-, 800-mg doses than after the 100-mg dose.
600-, and Clr did not differ Linear regression
with dose. of AUC, Cmax, and Aa versus dose resulted in statistically significant (P .05). Microbiologic and HPLC parameter estimates for AUC, lated (r> and HPLC
Pharmacokinetic Cefpodoxime Dose Marie
and Tolerance after Singleand Oral Administration Cefpodoxime Proxetil
T. Bonn,
PhD, Max
George
S. Hughes,
MD,
E. foyer,
MS, and
K. Sue
Cefpodoxime proxetil, a third generation, ministered in single doses of 100, 200, 400, ime equivalents) and multiple doses of 100, teers. The pharmacokinetics of the active
FCP,
metabolite,
Rajendra
Cathcart,
broad-spectrum, 800
600, and 200, and
Studies Multipleof
oral
cefpodoxime,
BS,
BS was
cephalosporin,
mg (dose expressed
400 mg twice
K. Patel,
of
ad-
as cefpodox-
daily to healthy and tolerance
volun-
of cef-
podoxime cefpodoxime
proxetil were determined. Results from the single-dose study indicate that exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.
C
efpodoxime proxetil is a third generation, broadspectrum cephalosponin for oral use. It is a prodrug that is believed to be de-esterified in the intestinal epithelium by nonspecific esterases to yield its active metabolite, cefpodoxime.1’2 Cefpodoxime acts by binding to penicillin-binding proteins, thus interfering with bacterial cell wall synthesis.3 Its antibacterial spectrum includes staphylococci, streptococci, and gram-negative species (Citrobacter, Hemophilus, Klebsiella and Proteus spp). Cefpodoxime is not active against most anaerobes, Pseudomonas species, methicillin-resistant Staphylococcus, on Enterococcus.2’4
From mazoo,
the
Clinical
Michigan.
Pharmacokinetics
Pharmacokinetics
Unit,
Upjohn
Company,
for reprints:
Marie 1. Bonn,
(7215-24-2),
The
Company,
Upjohn
49007.
J ClIn Pharmacol
The
Address
1991;31:1137-1
145
Kala-
PhD. Clinical Kalamazoo,
Ml
Pharmacokinetic studies of cefpodoxime in humans after oral administration of single 200-mg doses of cefpodoxime pnoxetil have shown that the drug is rapidly absorbed (absorption half-life of approximately 1 hr) and has a terminal disposition half-life of approximately 2.1 hours.5 Approximately 37% of the administered dose of cefpodoxime proxetil is excreted renally as cefpodoxime.5 The current study evaluated the pharmacokinetics, dose proportionality, and tolerance of cefpodoxime proxetil after singleand multiple-dose oral administration
of cefpodoxime
proxetil
to normal
vol-
unteers. Plasma samples that were collected in this study were assayed for cefpodoxime concentration by both microbiologic and high-pressure liquid chromatography (HPLC) methods, and the resulting assay concentrations and pharmacokinetic parameters were compared to determine how closely the microbiologic assay results agreed with those from the specific HPLC method.
1137
BORIN
800 mg (n = 7). In the multiple-dose study, 32 subjects were randomly assigned to the following treatment groups: placebo (n 8), 200 mg/day (n = 8), 400 mg/day (n = 8), or 800 mg/day (n = 8). These ran-
METHODS Subjects
=
Eighty-two
healthy
adult
volunteers
participated
in
the singleand written informed had
normal
trocardiograms, stool
multiple-dose studies after giving consents and medical histories; all results of physical examinations, elecclinical laboratory tests (including
specimens
to verify
absence
of toxin
to Clostrid-
ium difficile), and a negative surface antigen to hepatitis B, and all were drugfree as determined by a urine drug screen. Subjects did not have a history of hypersensitivity were not to
to penicillins or cephalosporins taken any other medications, for 10 days before the start
have
cluding antibiotics, study. Participants tions, other than
were not allowed the study medication,
and inof the
any medicathroughout
the
study. Subjects (33 men, 17 women) in the single-dose study ranged in age from 19 to 45 years and in body weight from 46 to 102 kg. Thirty-two male volunteers ranging in age from 24 to 51 years and in body weight from 58 to 98 kg, participated in the multipledose study. Subject demographics by treatment group are given in Table I.
Study
study, groups: 8), 400
=
50 subjects were randomplacebo (n = 11), 100 mg (n mg (n = 8), 600 mg (n = 8), or
TABLE I Subject Demographics Study! Treatment Group
domized, double-blind, were conducted according Drug
Administration
Each
subject
by Treatment Age (yr)*t
Male/Female
Single Dose Placebo 100 mg 200 mg 400 mg 600 mg 800 mg Multiple Dose Placebo 200 mg/day 400 mg/day 800 mg/day Mean ± SD. Statistically significant mg/day treatment groups.
6/5 4/4 5/3 6/2 7/1 5/2
29.9 30.0 27.7 29.3 26.6 33.4
8/0 8/0 8/0 8/0
34.1 38.6 28.3 33.5
difference
(P < .05)
± ± ± ± ± ±
Group Weight (kg)s
7.8 7.4 7.5 7.3 6.2 10.7
73.7 70.3 72.6 76.6 69.7 73.4
±
7.2 6.5 4.6 8.0
75.4 75.7 69.3 74.5
± ±
± ± ± ±
between
400
mg/day
± ± ± ± ±
± ±
13.1 15.0 15.2 12.8 15.1 9.4 11.7 9.2 7.7 10.0
and 200
Treatments
#{149} J Clin Pharmacol
1991;31:1137-1145
single-dose
were
study
administered
in the appropriate doxime proxetil
trials design.
received
either
24,832,
as film-coated
combination of placebo 100-mg tablets (Lots Kalamazoo, MI) with
Upjohn,
tablets
and cefpo24,767 and 240 mL of
water. Clinical Safety made
vated
Observations laboratory before and
and and
Laboratory
clinical
Tests
observations
were
24 hours after dosing in the singleAll safety laboratory studies were cona 12-hour fast. These included hematol-
blood count, thromboplastin
partial
prothrombin time, actitime, fibrinogen, direct
Coombs’ test), chemistry (multiple serum chemistry tests), and urinalysis. In addition, a 24-hour urine collection was done before and 24 hours after dosing.
An electrocardiogram was done with the aforementioned safety laboratory studies before dosing and again at .24 hours after dosing. Cardiac telemetry was done 24 hours before and for 24 hours after dosing. Audiometry (Bekesy audiometer, Industrial Acoustics, Bronx, NY) was done before and for 24 hours after dosing. Special laboratory tests included a template bleeding time (Simplate II, General Diagnostics, Durham, NC) which was done on the volunteer’s forearm prior to dosing, 2 hours after dosing (which was the expected peak plasma level), and again at 24 hours after dosing. Vital signs were measured before and at 2, 8, 12, 24, 36, and 48 hours after dosing. Volunteers were asked about adverse medical events at the same time vital signs were collected. The same panel of clinical tests and observations were done on volunteers in the multiple-dose study as for those in the single-dose study. All of the safety laboratory studies were collected after a 12-hour fast before and 24 hours after the first and last doses, and every 3 days while on the study. A 24-hour urine
collection
1138
in the
placebo-controlled to a parallel
placebo, or 100, 200, 400, 600, or 800 mg of cefpodoxime proxetil (dose expressed as cefpodoxime equivalents). Participants in the multiple-dose study received either placebo or 100, 200, or 400mg of cefpodoxime proxetil every 12 hours for 141/2 days.
dose study. ducted after ogy (complete
Design
In the single-dose ized to six dose 8), 200 mg (n
t
ET AL
was
done
before
and
after
the
first
and
last
PHARMACOKINETICS
doses. hours
Audiometry after the first
was performed and last doses
AND
before on day
and
TOLERANCE
and 24 7 (mid-
point of dosing regimen). Vital signs were measured on each day of the study, before dosing and twice daily thereafter. After the first and last doses of the study, vital signs were also taken at 2, 8, 12, 24, 36, and 48 hours after dosing. A template bleeding time was done as in the single-dose study on the first and last
days
of the
Specimen
study.
Collection
OF
Specimens trifuged
samples
(5 mL)
were
PROXETIL
immediately
placed
on ice and
cen-
3000 rpm for 6 minutes at 4#{176}C.The plasma was harvested, split, frozen immediately on dry ice, and stored at -70#{176}C until analysis. Urine was collected before dosing and each time the subject voided over the 48-hour period after drug
at
administration
in the
single-dose
study.
Urine
was
collected before dosing and at the following collection intervals after the first (day 1) and last (day 15) doses in the multiple-dose study: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 10, and 10 to 12 hours. After each void, the
time Blood
CEFPODOXIME
of collection
and
urine
weight
were
recorded.
A
for determination of cefpodoxime concentrations were collected at 0 hour (before drug administration), and at 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after drug administration in the single-dose study. In the multiple-dose
5-mL aliquot dry ice bath
study, blood samples drug administration),
Concentrations of cefpodoxime in plasma and urine were determined using reversed-phase high-pressure liquid chromatography (HPLC) methods and a microbiologic assay. In the HPLC plasma procedure,
were taken at 0 hour (before and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the first dose on day I and after the last dose on day 15. Additional samples were collected on day 15 at 16, 20, and 24 hours.
Analytical
of each collection was frozen using and stored at -70#{176}C until analysis.
a
Methods
samples
were
acidified
with
12
14
16
18
a phosphoric
acid
solu-
7
6 E
5
‘a
4
3
CD
= 03
‘a =
2
C C.,
1 0
0
2
4
6
8
10
Time After Drug Administration Figure 400
1. Average mg;
.
600
ANTI-INFECTIVE
plasma cefpodoxime mg; D, 800 mg.
concentrations
after
single-dose
administration
20
22
24
(hr)
of cefpodoxime
proxetil.#{149}, 100 mg; & 200
mg:#{149},
1139
BORIN
tion that contained internal standard (7-fl-hydroxyethyltheophylline) and extracted onto C8 reversedphase cartridges using an advanced automated sample processor (AASP). The absorbed drugs were eluted directly from the cartridges onto a C18 column using a mobile phase consisting of 0.05 M sodium acetate buffer (pH 5.2) and acetonitrile in a ratio of 93:7 (vol/vol). The eluate was monitored using UV detection at 254 nm. The linear range for analysis of cefpodoxime in plasma was 0.02 to 10 mcg/mL. The between-day coefficient of variation (CV) ranged from 25% for the low standard to 1.9% for the high standard. Assay precision, expressed as the CV of estimated concentration of quality control (QC) samples, ranged from 7.0% for the low (0.1 mcg/mL) QC sample to 2.5% for the high (4.0 mcg/mL) QC sample. Recovery was 96 to 100% in plasma. Urine cefpodoxime concentrations were determined by direct injection of filtered urine samples onto a C18 guard column using a mobile phase of 0.2% phosphoric acid (pH 2.0) and methanol in a ratio
of
90:10
(vol/vol).
After
a loading
period,
the
guard column was switched into the analytical stream, and the eluent was chromatographed on a C18 column using the mobile phase described earlier in the plasma analysis. Standard curves in urine were linear over the concentration range of 0.1 to 50 mcg/mL. The betweenday CV ranged from 24% for the low standard to 5%
ET
AL
for the high standard. Assay precision ranged from 2.9% for the 1.0 mcg/mL QC sample to 4.5% for the 24.5 mcg/mL QC sample. Recovery was 100 to 103% in urine. Quantitation of cefpodoxime in plasma was determined using a previously described microbiologic assay with Providencia rettgeri as the test organism.5’6
Linearity
was
established
over
the
cefpodox-
ime concentration range of 0.04 to 1.28 mcg/mL. Plasma samples were diluted with pooled plasma, as necessary, to obtain a linear standard curve. The assay showed a mean recovery of 94% and a maximum within-run precision (CV) of 3.9% and a betweenday CV of 8.0%. Pharmacokinetic
Analysis
Cefpodoxime pharmacokinetic parameters were determined by noncompartmental methods.7 Elimination rate constants (Xj were estimated by leastsquares regression of plasma cefpodoxime concentration-time data points lying in the terminal log-linear region of the curves. Elimination half-life (t112) was calculated as 0.693/X. Areas under the plasma concentration-time curve (AUC) and under the first moment curve (AUMC) were calculated by the trapezoidal rule. AUC and AUMC from time zero to infinity were obtained by adding extrapolated areas (AUCT_ and AUMCT_cc,, respectively) to AUC and AUMC determined from time zero to the time of
TABLE II Average
(SD) Cefpodoxlme Pharmacokinetic Parameters After Single-Dose Oral Administration of Cefpodoxlme Proxetil Dose
Parameter
AUC (mcg. hr/mL) Dose-normalized AUC (mcg.hr/mL) CIA/F (mL/min) Cmax (mcg/mL) Dose-normalized
mg
100
7.38
.1 ClIn
400
mg
(2.85)
13.1 (3.64)
22.7
7.38(2.85) 249 (71.2) 1.45 (0.46)
6.56(1.82) 268 (61.9) 2.34 (0.76)
5.67(1.23) 305 (58.2) 3.72 (0.97)
1.45 (0.46) 2.0 (0.67) 4.12 (0.61) 0.33 1 (0.074) 2.1 39.5 (4.9) 97.6 (30.1)
* Dose expressed as cefpodoxime equivalents; except n = 7 for 800-mg dose group.
S
mg
(4.90)
600 mg
35.8
(6.04)
5.96(1.01) 288 (55.7) 5.31 (1.20)
800 mg
44.3
(7.55)
5.54(0.95) 309 (54.2) 6.61 (1.64)
Cmax
(mcg/mL) Tmax (hr) MRT (hr) X2 (hr) Half-life (hr)t F (%) Cir (mL/min)
1140
200
*
Pharmacol
1991;31:1137-1
n
=
1.17 2.3 4.76 0.283
(0.38) (0.46) (0.69) (0.082) 2.5 32.3 (6.5) 84.4 (17.4)
8 subje cts per dose group,
145
0.93 2.6 5.31 0.244
(0.24) (0.82) (0.85) (0.035) 2.8 32.3 (5.3) 96.0 (10.6)
Harmonic
mean.
0.89 3.3 5.71 0.252
(0.20) (1.3) (1.03) (0.066) 2.8 30.0 (5.0) 84.7 (13.3)
0.83 2.9 5.68 0.220
(0.21) (0.69) (0.78) (0.025) 3.2 26.8 (4.6) 81.2 (9.89)
PHARMACOKINETICS
AND
TOLERANCE
the last detectable sample concentration, T, or 12 hours for the first dosing interval in the multipledose study. Peak-plasma concentration (Cmax) and time-to-peak concentration (Tmax) were determined by inspection of individual subject concentration-time curves. Dose-normalized AUC and Cmax were estimated by normalizing values to the 100-mg dose. Mean residence time (MRT) was calculated as AUMC/AUC. Apparent systemic clearance (Cl,/F) was estimated as dose/AUC. Drug accumulation in plasma after multiple dosing was calculated by dividing AUC at steady state by AUC for the first dosing interval (0-12 hr).8 Urinary excretion of cefpodoxime was determined by multiplying urine concentrations by the corresponding urine volumes. Cumulative urinary excretion (Ae) was calculated by summing the amounts of drug excreted at each of the collection intervals. Fe, the fraction of the administered dose excreted in the urine, was determined as Ae divided by the dose. Estimation of renal clearance (Clr) is given by A0 /AUC.
Cefpodoxime from
the
plasma
single-dose
study
concentration-time were
fitted
data to a one-com-
partment or two-compartment pharmacokinetic model with first-order absorption and elimination using RSTRIP.9 Weighting functions of 1, 1/C1, and 1/C12 were used, where C1 is the plasma concentration at time t. Goodness of fit for the different weights and models was determined by visual examination and by comparison of values for the model selection criteria
(MSC),
as defined
by
Fox.9
Differences in cefpodoxime pharmacokinetic parameters among dosing groups were investigated using a one-way analysis of variance (ANOVA) model. When the P-value for the ANOVA was statistically significant (P < .05), the LSD procedure was used for pairwise comparison of treatment means. A paired t-test procedure was used to determine the statistical significance of pharmacokinetic parameter differences between analogous first-dose and last-dose (steady-state) data within treatment groups in the multiple-dose study. Correlations between microbiologic and HPLC plasma assay results were examined using
simple
least-squares
regression
analysis.
RESULTS Single-Dose
PROXETIL
cokinetic parameters and dose-normalized Cmax showed statistically significant among treatments for Cmax, Tmax, X Dose-normalized Cmax was significantly the 400-, 600-, and 800-mg doses than for dose. This same trend was observed with malized AUC (AUG values after the 400-, 800-mg
doses
were
23-25%
100-mg dose), but these cally significant. Tmax significantly
higher
lower
than
differences after the
than
that
AUC and differences and MRT. lower after the 100-mg dose-nor600-, and
that
after
the
were not statisti600-mg dose was
after
the
100-
or 200-
mg dose. MRT also increased with dose, as evidenced by statistically significant differences in pairwise comparisons between the low (100- and 200-mg) and high (400-, 600-, and 800-mg) doses. The half-life of cefpodoxime appeared to increase with dose. However, only differences in X between the 100-mg and 400-,
600-,
cant.
F0 was
or 800-mg doses were statistically signifi18 to 32% lower after the 200-, 400-, 800-mg doses than after the 100-mg dose.
600-, and Clr did not differ Linear regression
with dose. of AUC, Cmax, and Aa versus dose resulted in statistically significant (P .05). Microbiologic and HPLC parameter estimates for AUC, lated (r> and HPLC
