Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. E, 21-28
Pharmacokinetics of cefpodoxime in young and elderly volunteers after single doses D. Tremblay, A. Dupront, C. Ho, D. Coussediere and B. Lenfant
Roussel Uclaf, Direction Recherches Santi, 93230 Romainville, France
Introduction
Cefpodoxime proxetil is a new third generation cephalosporin whose carboxyl function on the cephem nucleus has been esterified by an isopropyloxycarbonyloxyethyl group in order to enhance its absorption after oral administration. It is the free cefpodoxime that possesses the antibiotic activity and this must be released by hydrolysis of the ester for this activity to manifest itself: 130mg of cefpodoxime proxetil releases 100 mg of cefpodoxime. In this text, the doses will be expressed as cefpodoxime equivalent. The mechanism of absorption has been studied in the rat. Cefpodoxime proxetil was absorbed in the upper part of the gut and then hydrolysed during its passage through the intestinal wall so that only cefpodoxime reached the portal venous blood. The esterases that release cefpodoxime by hydrolysis are not specific to the gut wall and are also found in the liver and plasma (Komai el al., 1988). Studies have shown that cefpodoxime is bactericidal in vitro with very low MICs for the majority of Gram-positive cocci and Gram-negative bacteria. It is particularly active against respiratory pathogens (Wise et al., 1990). This paper reports three pharmacokinetic studies in healthy volunteers after single dose administration of cefpodoxime proxetil. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and the pharmacokinetic parameters of 21 0305-7453/90/26E021 +08 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Three pharmacokinetic studies involving single oral doses of cefpodoxime proxetil in healthy volunteers are reported. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and pharmacokinetic parameters of cefpodoxime, and the third was to compare the pharmacokinetics of cefpodoxime in healthy young and elderly volunteers. Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine. The volume of distribution is large (32-3 1). The pharmacokinetics of cefpodoxime were linear in young and elderly subjects after 100 and 200 mg oral doses, which are those used therapeutically. The C^ was about l-4mg/l (after lOOmg) and 2-6mg/l (after 200 mg). Deviation from linearity appeared at 400 mg and the effect was confirmed at 800 mg. The differences between young and elderly subjects were negligible, with the exception of the half-life which increased by only 14%, from 2-67 to 3h. Dosage adjustment is therefore not necessary in the elderly.
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cefpodoxime and the third was to compare the pharmacokinetics of cefpodoxime in the young and elderly.
Metbods Subjects
Treatments In the first study, subjects received two treatments: lOOmg iv in a 2 h infusion at a constant rate and then 100 mg orally as one tablet. In the second study, subjects received four treatments: 100, 200, 400 and 800 mg oral doses as 1, 2, 4 and 8 tablets. In the third study, young subjects who constituted the reference group received only one treatment: 100 mg orally. The elderly subjects received two treatments: 100-200 mg oral doses as 1-2 tablets. When there was more than one treatment, these were allocated by a balanced cross-over randomization plan (mixed latin square design). Collection of samples Blood samples were collected in tubes containing dry lithium heparin. Fifteen to 18 samples were drawn up to 16 or 24 h post dose, depending on the study. Urine was collected over a 24 h period. Plasma and urine were frozen at — 20°C until assay. Assay procedure Concentrations of cefpodoxime were measured in urine and plasma by HPLC. The column was /iBondapak C18 and detection was by uv absorption at 254 nm. Initially both plasma and urine were adsorbed on to a Cl8 cartridge on an AASP Prep station. The cartridge was initially washed with dilute sulphuric acid and the cefpodoxime was then eluted with mobile phase, mixed with an internal standard and analysed. For plasma the mobile phase was 0-05 M acetate buffer pH 4-6: acetonitrile (93:7) and for urines it was citrate buffer pH 3-5: acetonitrile (92:8). The limits of quantification for a 0-25 ml sample were 0-02 and 2 mg/1 in plasma and urine respectively. The assays were performed in independent series. Each series comprised a calibration range, plasma or urine samples from all the treatments of one or several subjects and a
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Twelve healthy young volunteers between 18 and 48 years old were admitted to each study. In addition, twelve healthy elderly volunteers aged between 67 and 77 years were admitted to the third study. Their weight did not vary by more than 15% from the ideal weight. Allowing for their age, they were normal on medical examination which included clinical laboratory investigation and 12 lead electrocardiogram. The protocols were approved by local ethics committees. Each volunteer was fully informed of the purpose and the possible risk of the study, and gave his informed consent. Cefpodoxime was given as 100 mg equivalent cefpodoxime proxetil tablets or as cefpodoxime sodium salt solution (absolute bioavailability). The oral drug was taken in the morning, and all the subjects had fasted since the previous night and for 2 h after administration. Tablets were swallowed with 150 ml water.
Single dose phannacokinetfcs
23
control every ninth sample. Calibration range and control samples were prepared separately with pooled human plasma or urine spiked with a known concentration of cefpodoxime. The coefficients of variation of the control plasma were 8-1-108%, 6-48-4% and 6-4-8-3% for 0 1 , 0 5 and 2 mg/1, respectively. Those of the control urine were 3-4-106%, 31-5-2% and 3-5-6-0%, for 5, 20 and 80 mg/1, respectively. Pharmacokinetics
Statistics Differences between young and elderly subjects were tested by a one way analysis of variance (ANOVA). In the other cases, results were submitted to a three-way analysis of variance: treatment, subject and period effect. When there were more than two treatments, treatment effect was tested by a Tukey test using the residual of ANOVA.
Results All samples were obtained as planned in the protocols, except for one urine collection which was incomplete for one subject after iv treatment. The mean cefpodoxime plasma concentrations by time are given in Figure 1 (first study), Figure 2 (second study) and Figures 3 and 4 (third study). When cefpodoxime was administered iv, C , ^ and T^ were reached at the end of infusion, as expected. C ^ , was followed by a short distribution phase which was not detectable after oral administration. The kinetic parameters are shown in Tables I, II and III. There was no significant difference between Clr and Tl/2 depending on the administration route. C ^ , AUC and U increased with the dose in young and elderly subjects. As shown by statistical analysis of these parameters normalized by the dose, the increase was proportional to the dose after 100 and 200 mg doses but was lower than expected with the larger doses. In addition, Cl, decreased and Tt/2 increased with the larger doses. There was no statistical difference between young healthy and elderly subjects, except for r , p which increased with age. Mean±s.E.M. of the absolute bioavailability in terms of the amount of cefpodoxime
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Maximum plasma concentration ( C ^ and time to reach Cnax (T^ were obtained from the data review. The area under the plasma concentration curve ( A U Q was calculated by the trapezoidal rule. The amount excreted unchanged in urine (U) was obtained by multiplying the concentration by the volume of urine. Renal clearance (C/r) was calculated by: C/r = U/AUC. A biexponential function, representative of either the distribution and elimination phases after the end of the infusion or the absorption and elimination phases after oral administration was fitted to the data to estimate the plasma elimination constant rate (&J. Elimination half-life (r l / 2 ) was calculated by: r,/2 = 1 a2/kt. Total clearance (C/), extrarenal clearance (Cla) and volume of distribution (V) were calculated from the iv data: Cl = dose/AUC, Cla = Cl-Cln V = Cl/kt. The fraction of cefpodoxime dose reaching the body (F, absolute bioavailability) was calculated by three different methods; the ratio of AUC, the ratio of U, and plasma and urinary data: ( A U C ^ x Cla+ t/^J/dose (Kwan & Till, 1973). Parameters expected to be proportional to the dose were normalized by the dose: C^/dose, AUC/ dose, U/dose.
D. Tremblay et al.
24
Figure 1. Mean±s.E.M. of the plasma concentrations of cefpodoxime in mg/1 after administration of a single dose equivalent to 100 mg of cefpodoxime iv, cefpodoxime sodium salt by infusion in 2 h at a constant rate (O). oral, cefpodoxime proxetil in tablet form (D)-
reaching the body was 45-9± 1-5% using the AUC ratio, 53-3±3-9% using the U ratio and 51-5 ±3-2% using plasma and urinary data. Discussion Conventionally, absolute bioavailability is calculated from the AUC or U ratio. This assumes in the first case that Cl and hence Cla+Clr remain the same between iv and oral administration and in the second that the ratio Cl, to Cl remains the same between 10-000
o-ooi
10
12 14 Time (h)
20
22
24
Figure 2. Mean ±S.E.M. of the plasma concentrations of cefpodoxime after administration of a single oral dose of cefpodoxime proxetil equivalent to 1 0 0 ( # ) , 200 ( • ) , 400 (A), and 8 0 0 ( * ) m g o f cefpodoxime to 12 healthy volunteers.
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0-01
Single dose phannacoklnetics
25
0-01 -
0-001
10
12 M Time (h)
18
24
Figure 3. Mean ±5^.w. of the plasma concentrations of cefpodoxime after administration of a single oral dose of cefpodoxime proxetil equivalent to lOOmg of cefpodoxime to 12 young healthy volunteers ( • ) and 12 elderly healthy volunteers ( • ) .
iv and oral administrations. In the third method used here (Kwan & Till, 1973), there is no assumption about C/n which may vary from one administration to another. Only Cla is assumed to remain constant. It is a valuable method when Cl, is large in relation to C ^ as in the case of cefpodoxime. The estimations are consistent, within the limits of experimental error, the most reliable usually being the one that requires the fewest hypotheses, i.e. the method taking plasma and urinary data into account. Half the dose of cefpodoxime administered
0-01 -
0-001
10
12 14 Time (h)
24
Figure 4. Mean ± S^M. of the plasma concentrations of cefpodoxime after administration of two single oral doses of cefpodoxime proxetil equivalent to 100 ( • ) and 200 ( • ) m g of cefpodoxime to 12 elderly healthy volunteers.
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S
o
D. Tremblay et aL
26
TaWe I. Mean ± SEM, and summary of ANOVA of the pharmacokinetic parameters of cefpodoxime after administration of a dose equivalent to 100 mg of cefpodoxime
iv Oral ANOVA cefpodoxime cefpodoxime effect of route sodium salt proxetil of administration (mg/1)
t
ND 4 b
NS NS
n - 12 except' n = 11. ANOVA, Summary of analysis of variance. N S / > > 005; •/»< 0-001. ND, not done.
orally as cefpodoxime proxetil reaches the systemic circulation. It is slightly higher than the 36% bioavailability of cefuroxime orally administered as the cefuroxime axetil ester prodrug (Finn et al., 1987). There is some evidence in the literature that the bioavailability of prodrug esters is improved with meals. Based on the comparison of the AUC, that of cefpodoxime is improved by 22%-34% (Hughes et al., 1989) and that of cefuroxime by 45% (Finn et al., 1987). The results obtained after intravenous administration also enable other basic pharTable II. Mean ± S.E.M. of the pharmacokinetic parameters for 12 healthy volunteers of cefpodoxime obtained after administration of a single oral dose of cefpodoxime proxetil expressed as the equivalent cefpodoxime dose 100
Cm« (mg/1) AUC (mg.h/1) U(mg) C/r G/h) 7*. (h)
1-367 ±0-079 2-36±O13 703 ± 0 5 3 40-2 ± 2 0 5.87 ± 0 2 8 211 ± 0 0 7
((mg/l)/mg) O014±O001 AUC/dose ((mg.h/l)/mg) 0O70±0O05 U/dose (mg/mg) O402±O020
Cefpodoxime dose (mg) 200 400
ANOVA dose effect
800
2-60±O16 2-42±O15 14-5 ± 1 0 78-5 ±3-5 5-59 ± 0 4 0 2-31 ± 0 1 5
4-50 ± 0 2 7 2-50±O17 26-5 ±1-3 95-2 ±7-8 3-64±O30 2-42±O17
6-95 ± 0 3 4 2-94 ± 0 2 9 46-4±l-5 224 ±19 4-75 ± 0 3 0 2-88 ± 0 2 1
MOO 200 400 800 NS MOO 200 400 800 MOO 200 400 800
0O13±O001
0011 ±0001
O009±O000
t
0O73±0O05
0066±0003
0058±0002
«800_400JOP_200
0.392±0O18
O238±0O19
O279±0O24
MOO 800 200 100
>400 800 200 100 MOO200 400 800 800 400 200 100
ANOVA, Summary of analysis of variance. NS: P > 005, «005 > P > 001; */» < 0O01. When the dose effect was significant, the means identified by the corresponding dose were classified in ascending order and compared by Tukey't test. The means underscored with the same line do not differ significantly from one another.
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2-97±0-13 O96±0O7 2.00 2-25±0-19 Tm(h) AUC (mg.h/1) 10-30±O41 4-75 ±0-28 U ' (mg) 80-5 ±4-7 42-8 ±3-8 806 ±0.44 9-46±0-81 Ci; (l/h) 9-88 ±0-39 — a (i/h) 209 ±0-48 — cia' G/h) 2-296 ± 0 0 8 0 2-421 ±0-080 V(\) 32-3 ±1-6 — C^
Single dose pharmaraktnertrs
27
Table HI. Mean ± S.E.M. of the pharmacolrinetic parameters for 12 young and 12 elderly healthy volunteers of cefpodoxime obtained after administration of a single oral dose of cefpodoxime proxctil expressed as the equivalent cefpodoxime dose ANOVA Volunteers young elderly young/elderly elderly dose 100 mg dose 100 mg dose 200 mg 100/100 100/200 NS NS NS NS NS — — —
C
NS » c
NS NS NS NS NS
ANOVA, Summary of analysis of variance: young/elderly 100/100: effect of age, at equal doses, elderly 100/ 300: effect of dose in elderly subjects. NS: P > 005; "005 > />>{K)1; *0Ol > P> 0-001; 'P< 0O01.
macokinetic characteristics of cefpodoxime to be determined. The mean volume of distribution (32-31) is very high for a cephalosporin, and corresponds to the good tissue penetration observed in inflammatory fluids (O'Neil et al., 1990), tonsils (Gehanno et al., 1990), pleural fluid (Dumont et al., 1990) and lung (Couraud et al., 1990). The amount eliminated unchanged in the urine is also a very high value (mean 80-5 mg) showing that cefpodoxime is metabolised very little and that its biliary elimination is marginal. In young and elderly subjects, the pharmacokinetics of cefpodoxime were linear after the 100 and 200 mg doses, which are the therapeutic doses. Larger doses given to the young subjects showed a slight lack of linearity occurring after 400 mg. That was confirmed after 800 mg, at which dose the plasma concentrations and urinary elimination were below those expected, and the elimination half-life was longer. These results are in agreement with the first Japanese results (Kobayashi et al., 1988; Saito, 1988). The differences between young and elderly subjects were negligible with the exception of the half-life, which increased by only 14% from 2-67 to 3 h. That, however, was sufficient for the plasma concentration at 12 h to be double in the elderly subjects, 0-181 as against 0098mg/1 (lOOmg dose), whereas the C ^ was the same. As usual for cephalosporins, these differences are not clinically relevant (Meyers & Wilkinson, 1989). Thus, dosage adjustment is not necessary in the elderly. Acknowledgements We thank the following for their collaboration in the clinical aspects of this work: Dr A. Surjus, Roussel Uclaf, Romainville, France; Dr A. Sutton, Roussel Labs, Swindon, UK; Dr H. Antrobus, Hazleton Medical Research Unit, Leeds, UK. References Couraud, L., Andrews, J. M., Lecoeur, H., Sultan, E. & Lenfant, B. (1990). Concentration of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil. Journal of Antimicrobial Chemotherapy 26, Suppl. E, 35-40.
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
1-32±O11 1-4410-20 2-5910-34 2-38±O18 2-92±0-33 2-7110-19 AUC (mg.h/1) 7-27 ±0-81 90111 16-612-3 U(mg) 38-4 ±3-5 37-0±2-4 72-5150 Cl, (l/h) 5-50 ±0-43 4-41±0-35 4-8210-43 7-j(h) 2-6710-12 3-0710-11 30010-16 C^dose ((mg/l)/mg) — 001410002 0O1310O02 AUC/dose ((mg.h/l)/mg) — 009010011 0O8310O12 U/dose (mg/mg) — 0-37010O24 0-36310O25 C M (mg/1)
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and Chemotherapy 34, 232—4.
Saito, A. (1988). Pharmacokinetic study on CS-807. Chemotherapy (Tokyo) 36, Suppl. 1 252-60. Wise, R., Andrews, J. M., Ashby, J. P. & Thornber, D. (1990). The in-vitro activity of cefpodoxime: a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50.
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Dumont, R., Uuetat, F., Andrews, J. M., Sultan, E. & Lenfant, B. (1990). Concentrations of ccfpodoxime in plasma and pleura! fluid after a single oral dose of cefpodoxime proxctil. Journal of Antimicrobial Chemotherapy 26, Suppl. E, 41-6. Finn, A., Straughn, A., Meyer, M. & Chubb, J. (1987). Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharmaceutics and Drug Disposition 8, 519-26. Gehanno, P., Andrews, J. M., Ichou, F., Sultan, E. & Lenfant, B. (1990). Concentrations of cefpodoxime in plasma and tonsillar tissue after a single oral dose of cefpodoxime proxetil. Journal of Antimicrobial Chemotherapy 26, Suppl. E. 47-51. Hughes, G. S., Heald, D. L., Barker, K. B., Patel, R. K., Spillers, C. R., Watts, K. C. et al. (1989). The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clinical Pharmacology and Therapeutics 46, 674-85. Kobayashi, S., Koguchi, K., Uchida, E., Yasuhara, H., Sakamoto, K., Sekine, M. et al. (1988). Phase I clinical study of CS-807, a new oral cephalosporin. Chemotherapy (Tokyo) 36, Suppl. 1, 200-14. Komai, T., Kawai, K., Tsubaki, H., Tolcui, T., Kinoshita, T. & Tanaka, M. (1988). Absorption, distribution, metabolism and excretion of CS-807, a new oral cephem antitiobic, in experimental animals. Chemotherapy (Tokyo) 36, Suppl. 1, 229-40. Kwan, K. C. & Till, A. E. (1973). Novel method for bioavailability assessment. Journal of Pharmaceutical Sciences 62, 1494-7. Meyers, B. R. & Wilkinson, P. (1989). Clinical pharmacokinetics of antibacterial drugs in the elderly. Implication for selection and dosage. Clinical Pharmacokinetics 17, 385-95. O'Neill, P., Nye, K., Douce, G., Andrews, J. & Wise, R. (1990). Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. Antimicrobial Agents
Pharmacokinetics of cefpodoxime in young and elderly volunteers after single doses D. Tremblay, A. Dupront, C. Ho, D. Coussediere and B. Lenfant
Roussel Uclaf, Direction Recherches Santi, 93230 Romainville, France
Introduction
Cefpodoxime proxetil is a new third generation cephalosporin whose carboxyl function on the cephem nucleus has been esterified by an isopropyloxycarbonyloxyethyl group in order to enhance its absorption after oral administration. It is the free cefpodoxime that possesses the antibiotic activity and this must be released by hydrolysis of the ester for this activity to manifest itself: 130mg of cefpodoxime proxetil releases 100 mg of cefpodoxime. In this text, the doses will be expressed as cefpodoxime equivalent. The mechanism of absorption has been studied in the rat. Cefpodoxime proxetil was absorbed in the upper part of the gut and then hydrolysed during its passage through the intestinal wall so that only cefpodoxime reached the portal venous blood. The esterases that release cefpodoxime by hydrolysis are not specific to the gut wall and are also found in the liver and plasma (Komai el al., 1988). Studies have shown that cefpodoxime is bactericidal in vitro with very low MICs for the majority of Gram-positive cocci and Gram-negative bacteria. It is particularly active against respiratory pathogens (Wise et al., 1990). This paper reports three pharmacokinetic studies in healthy volunteers after single dose administration of cefpodoxime proxetil. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and the pharmacokinetic parameters of 21 0305-7453/90/26E021 +08 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Three pharmacokinetic studies involving single oral doses of cefpodoxime proxetil in healthy volunteers are reported. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and pharmacokinetic parameters of cefpodoxime, and the third was to compare the pharmacokinetics of cefpodoxime in healthy young and elderly volunteers. Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine. The volume of distribution is large (32-3 1). The pharmacokinetics of cefpodoxime were linear in young and elderly subjects after 100 and 200 mg oral doses, which are those used therapeutically. The C^ was about l-4mg/l (after lOOmg) and 2-6mg/l (after 200 mg). Deviation from linearity appeared at 400 mg and the effect was confirmed at 800 mg. The differences between young and elderly subjects were negligible, with the exception of the half-life which increased by only 14%, from 2-67 to 3h. Dosage adjustment is therefore not necessary in the elderly.
22
D. Tremblay et aL
cefpodoxime and the third was to compare the pharmacokinetics of cefpodoxime in the young and elderly.
Metbods Subjects
Treatments In the first study, subjects received two treatments: lOOmg iv in a 2 h infusion at a constant rate and then 100 mg orally as one tablet. In the second study, subjects received four treatments: 100, 200, 400 and 800 mg oral doses as 1, 2, 4 and 8 tablets. In the third study, young subjects who constituted the reference group received only one treatment: 100 mg orally. The elderly subjects received two treatments: 100-200 mg oral doses as 1-2 tablets. When there was more than one treatment, these were allocated by a balanced cross-over randomization plan (mixed latin square design). Collection of samples Blood samples were collected in tubes containing dry lithium heparin. Fifteen to 18 samples were drawn up to 16 or 24 h post dose, depending on the study. Urine was collected over a 24 h period. Plasma and urine were frozen at — 20°C until assay. Assay procedure Concentrations of cefpodoxime were measured in urine and plasma by HPLC. The column was /iBondapak C18 and detection was by uv absorption at 254 nm. Initially both plasma and urine were adsorbed on to a Cl8 cartridge on an AASP Prep station. The cartridge was initially washed with dilute sulphuric acid and the cefpodoxime was then eluted with mobile phase, mixed with an internal standard and analysed. For plasma the mobile phase was 0-05 M acetate buffer pH 4-6: acetonitrile (93:7) and for urines it was citrate buffer pH 3-5: acetonitrile (92:8). The limits of quantification for a 0-25 ml sample were 0-02 and 2 mg/1 in plasma and urine respectively. The assays were performed in independent series. Each series comprised a calibration range, plasma or urine samples from all the treatments of one or several subjects and a
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Twelve healthy young volunteers between 18 and 48 years old were admitted to each study. In addition, twelve healthy elderly volunteers aged between 67 and 77 years were admitted to the third study. Their weight did not vary by more than 15% from the ideal weight. Allowing for their age, they were normal on medical examination which included clinical laboratory investigation and 12 lead electrocardiogram. The protocols were approved by local ethics committees. Each volunteer was fully informed of the purpose and the possible risk of the study, and gave his informed consent. Cefpodoxime was given as 100 mg equivalent cefpodoxime proxetil tablets or as cefpodoxime sodium salt solution (absolute bioavailability). The oral drug was taken in the morning, and all the subjects had fasted since the previous night and for 2 h after administration. Tablets were swallowed with 150 ml water.
Single dose phannacokinetfcs
23
control every ninth sample. Calibration range and control samples were prepared separately with pooled human plasma or urine spiked with a known concentration of cefpodoxime. The coefficients of variation of the control plasma were 8-1-108%, 6-48-4% and 6-4-8-3% for 0 1 , 0 5 and 2 mg/1, respectively. Those of the control urine were 3-4-106%, 31-5-2% and 3-5-6-0%, for 5, 20 and 80 mg/1, respectively. Pharmacokinetics
Statistics Differences between young and elderly subjects were tested by a one way analysis of variance (ANOVA). In the other cases, results were submitted to a three-way analysis of variance: treatment, subject and period effect. When there were more than two treatments, treatment effect was tested by a Tukey test using the residual of ANOVA.
Results All samples were obtained as planned in the protocols, except for one urine collection which was incomplete for one subject after iv treatment. The mean cefpodoxime plasma concentrations by time are given in Figure 1 (first study), Figure 2 (second study) and Figures 3 and 4 (third study). When cefpodoxime was administered iv, C , ^ and T^ were reached at the end of infusion, as expected. C ^ , was followed by a short distribution phase which was not detectable after oral administration. The kinetic parameters are shown in Tables I, II and III. There was no significant difference between Clr and Tl/2 depending on the administration route. C ^ , AUC and U increased with the dose in young and elderly subjects. As shown by statistical analysis of these parameters normalized by the dose, the increase was proportional to the dose after 100 and 200 mg doses but was lower than expected with the larger doses. In addition, Cl, decreased and Tt/2 increased with the larger doses. There was no statistical difference between young healthy and elderly subjects, except for r , p which increased with age. Mean±s.E.M. of the absolute bioavailability in terms of the amount of cefpodoxime
Downloaded from http://jac.oxfordjournals.org/ at New York University on April 24, 2015
Maximum plasma concentration ( C ^ and time to reach Cnax (T^ were obtained from the data review. The area under the plasma concentration curve ( A U Q was calculated by the trapezoidal rule. The amount excreted unchanged in urine (U) was obtained by multiplying the concentration by the volume of urine. Renal clearance (C/r) was calculated by: C/r = U/AUC. A biexponential function, representative of either the distribution and elimination phases after the end of the infusion or the absorption and elimination phases after oral administration was fitted to the data to estimate the plasma elimination constant rate (&J. Elimination half-life (r l / 2 ) was calculated by: r,/2 = 1 a2/kt. Total clearance (C/), extrarenal clearance (Cla) and volume of distribution (V) were calculated from the iv data: Cl = dose/AUC, Cla = Cl-Cln V = Cl/kt. The fraction of cefpodoxime dose reaching the body (F, absolute bioavailability) was calculated by three different methods; the ratio of AUC, the ratio of U, and plasma and urinary data: ( A U C ^ x Cla+ t/^J/dose (Kwan & Till, 1973). Parameters expected to be proportional to the dose were normalized by the dose: C^/dose, AUC/ dose, U/dose.
D. Tremblay et al.
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Figure 1. Mean±s.E.M. of the plasma concentrations of cefpodoxime in mg/1 after administration of a single dose equivalent to 100 mg of cefpodoxime iv, cefpodoxime sodium salt by infusion in 2 h at a constant rate (O). oral, cefpodoxime proxetil in tablet form (D)-
reaching the body was 45-9± 1-5% using the AUC ratio, 53-3±3-9% using the U ratio and 51-5 ±3-2% using plasma and urinary data. Discussion Conventionally, absolute bioavailability is calculated from the AUC or U ratio. This assumes in the first case that Cl and hence Cla+Clr remain the same between iv and oral administration and in the second that the ratio Cl, to Cl remains the same between 10-000
o-ooi
10
12 14 Time (h)
20
22
24
Figure 2. Mean ±S.E.M. of the plasma concentrations of cefpodoxime after administration of a single oral dose of cefpodoxime proxetil equivalent to 1 0 0 ( # ) , 200 ( • ) , 400 (A), and 8 0 0 ( * ) m g o f cefpodoxime to 12 healthy volunteers.
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0-01
Single dose phannacoklnetics
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0-01 -
0-001
10
12 M Time (h)
18
24
Figure 3. Mean ±5^.w. of the plasma concentrations of cefpodoxime after administration of a single oral dose of cefpodoxime proxetil equivalent to lOOmg of cefpodoxime to 12 young healthy volunteers ( • ) and 12 elderly healthy volunteers ( • ) .
iv and oral administrations. In the third method used here (Kwan & Till, 1973), there is no assumption about C/n which may vary from one administration to another. Only Cla is assumed to remain constant. It is a valuable method when Cl, is large in relation to C ^ as in the case of cefpodoxime. The estimations are consistent, within the limits of experimental error, the most reliable usually being the one that requires the fewest hypotheses, i.e. the method taking plasma and urinary data into account. Half the dose of cefpodoxime administered
0-01 -
0-001
10
12 14 Time (h)
24
Figure 4. Mean ± S^M. of the plasma concentrations of cefpodoxime after administration of two single oral doses of cefpodoxime proxetil equivalent to 100 ( • ) and 200 ( • ) m g of cefpodoxime to 12 elderly healthy volunteers.
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S
o
D. Tremblay et aL
26
TaWe I. Mean ± SEM, and summary of ANOVA of the pharmacokinetic parameters of cefpodoxime after administration of a dose equivalent to 100 mg of cefpodoxime
iv Oral ANOVA cefpodoxime cefpodoxime effect of route sodium salt proxetil of administration (mg/1)
t
ND 4 b
NS NS
n - 12 except' n = 11. ANOVA, Summary of analysis of variance. N S / > > 005; •/»< 0-001. ND, not done.
orally as cefpodoxime proxetil reaches the systemic circulation. It is slightly higher than the 36% bioavailability of cefuroxime orally administered as the cefuroxime axetil ester prodrug (Finn et al., 1987). There is some evidence in the literature that the bioavailability of prodrug esters is improved with meals. Based on the comparison of the AUC, that of cefpodoxime is improved by 22%-34% (Hughes et al., 1989) and that of cefuroxime by 45% (Finn et al., 1987). The results obtained after intravenous administration also enable other basic pharTable II. Mean ± S.E.M. of the pharmacokinetic parameters for 12 healthy volunteers of cefpodoxime obtained after administration of a single oral dose of cefpodoxime proxetil expressed as the equivalent cefpodoxime dose 100
Cm« (mg/1) AUC (mg.h/1) U(mg) C/r G/h) 7*. (h)
1-367 ±0-079 2-36±O13 703 ± 0 5 3 40-2 ± 2 0 5.87 ± 0 2 8 211 ± 0 0 7
((mg/l)/mg) O014±O001 AUC/dose ((mg.h/l)/mg) 0O70±0O05 U/dose (mg/mg) O402±O020
Cefpodoxime dose (mg) 200 400
ANOVA dose effect
800
2-60±O16 2-42±O15 14-5 ± 1 0 78-5 ±3-5 5-59 ± 0 4 0 2-31 ± 0 1 5
4-50 ± 0 2 7 2-50±O17 26-5 ±1-3 95-2 ±7-8 3-64±O30 2-42±O17
6-95 ± 0 3 4 2-94 ± 0 2 9 46-4±l-5 224 ±19 4-75 ± 0 3 0 2-88 ± 0 2 1
MOO 200 400 800 NS MOO 200 400 800 MOO 200 400 800
0O13±O001
0011 ±0001
O009±O000
t
0O73±0O05
0066±0003
0058±0002
«800_400JOP_200
0.392±0O18
O238±0O19
O279±0O24
MOO 800 200 100
>400 800 200 100 MOO200 400 800 800 400 200 100
ANOVA, Summary of analysis of variance. NS: P > 005, «005 > P > 001; */» < 0O01. When the dose effect was significant, the means identified by the corresponding dose were classified in ascending order and compared by Tukey't test. The means underscored with the same line do not differ significantly from one another.
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2-97±0-13 O96±0O7 2.00 2-25±0-19 Tm(h) AUC (mg.h/1) 10-30±O41 4-75 ±0-28 U ' (mg) 80-5 ±4-7 42-8 ±3-8 806 ±0.44 9-46±0-81 Ci; (l/h) 9-88 ±0-39 — a (i/h) 209 ±0-48 — cia' G/h) 2-296 ± 0 0 8 0 2-421 ±0-080 V(\) 32-3 ±1-6 — C^
Single dose pharmaraktnertrs
27
Table HI. Mean ± S.E.M. of the pharmacolrinetic parameters for 12 young and 12 elderly healthy volunteers of cefpodoxime obtained after administration of a single oral dose of cefpodoxime proxctil expressed as the equivalent cefpodoxime dose ANOVA Volunteers young elderly young/elderly elderly dose 100 mg dose 100 mg dose 200 mg 100/100 100/200 NS NS NS NS NS — — —
C
NS » c
NS NS NS NS NS
ANOVA, Summary of analysis of variance: young/elderly 100/100: effect of age, at equal doses, elderly 100/ 300: effect of dose in elderly subjects. NS: P > 005; "005 > />>{K)1; *0Ol > P> 0-001; 'P< 0O01.
macokinetic characteristics of cefpodoxime to be determined. The mean volume of distribution (32-31) is very high for a cephalosporin, and corresponds to the good tissue penetration observed in inflammatory fluids (O'Neil et al., 1990), tonsils (Gehanno et al., 1990), pleural fluid (Dumont et al., 1990) and lung (Couraud et al., 1990). The amount eliminated unchanged in the urine is also a very high value (mean 80-5 mg) showing that cefpodoxime is metabolised very little and that its biliary elimination is marginal. In young and elderly subjects, the pharmacokinetics of cefpodoxime were linear after the 100 and 200 mg doses, which are the therapeutic doses. Larger doses given to the young subjects showed a slight lack of linearity occurring after 400 mg. That was confirmed after 800 mg, at which dose the plasma concentrations and urinary elimination were below those expected, and the elimination half-life was longer. These results are in agreement with the first Japanese results (Kobayashi et al., 1988; Saito, 1988). The differences between young and elderly subjects were negligible with the exception of the half-life, which increased by only 14% from 2-67 to 3 h. That, however, was sufficient for the plasma concentration at 12 h to be double in the elderly subjects, 0-181 as against 0098mg/1 (lOOmg dose), whereas the C ^ was the same. As usual for cephalosporins, these differences are not clinically relevant (Meyers & Wilkinson, 1989). Thus, dosage adjustment is not necessary in the elderly. Acknowledgements We thank the following for their collaboration in the clinical aspects of this work: Dr A. Surjus, Roussel Uclaf, Romainville, France; Dr A. Sutton, Roussel Labs, Swindon, UK; Dr H. Antrobus, Hazleton Medical Research Unit, Leeds, UK. References Couraud, L., Andrews, J. M., Lecoeur, H., Sultan, E. & Lenfant, B. (1990). Concentration of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil. Journal of Antimicrobial Chemotherapy 26, Suppl. E, 35-40.
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1-32±O11 1-4410-20 2-5910-34 2-38±O18 2-92±0-33 2-7110-19 AUC (mg.h/1) 7-27 ±0-81 90111 16-612-3 U(mg) 38-4 ±3-5 37-0±2-4 72-5150 Cl, (l/h) 5-50 ±0-43 4-41±0-35 4-8210-43 7-j(h) 2-6710-12 3-0710-11 30010-16 C^dose ((mg/l)/mg) — 001410002 0O1310O02 AUC/dose ((mg.h/l)/mg) — 009010011 0O8310O12 U/dose (mg/mg) — 0-37010O24 0-36310O25 C M (mg/1)
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D. Tremblay et at.
and Chemotherapy 34, 232—4.
Saito, A. (1988). Pharmacokinetic study on CS-807. Chemotherapy (Tokyo) 36, Suppl. 1 252-60. Wise, R., Andrews, J. M., Ashby, J. P. & Thornber, D. (1990). The in-vitro activity of cefpodoxime: a comparison with other oral cephalosporins. Journal of Antimicrobial Chemotherapy 25, 541-50.
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Dumont, R., Uuetat, F., Andrews, J. M., Sultan, E. & Lenfant, B. (1990). Concentrations of ccfpodoxime in plasma and pleura! fluid after a single oral dose of cefpodoxime proxctil. Journal of Antimicrobial Chemotherapy 26, Suppl. E, 41-6. Finn, A., Straughn, A., Meyer, M. & Chubb, J. (1987). Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharmaceutics and Drug Disposition 8, 519-26. Gehanno, P., Andrews, J. M., Ichou, F., Sultan, E. & Lenfant, B. (1990). Concentrations of cefpodoxime in plasma and tonsillar tissue after a single oral dose of cefpodoxime proxetil. Journal of Antimicrobial Chemotherapy 26, Suppl. E. 47-51. Hughes, G. S., Heald, D. L., Barker, K. B., Patel, R. K., Spillers, C. R., Watts, K. C. et al. (1989). The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clinical Pharmacology and Therapeutics 46, 674-85. Kobayashi, S., Koguchi, K., Uchida, E., Yasuhara, H., Sakamoto, K., Sekine, M. et al. (1988). Phase I clinical study of CS-807, a new oral cephalosporin. Chemotherapy (Tokyo) 36, Suppl. 1, 200-14. Komai, T., Kawai, K., Tsubaki, H., Tolcui, T., Kinoshita, T. & Tanaka, M. (1988). Absorption, distribution, metabolism and excretion of CS-807, a new oral cephem antitiobic, in experimental animals. Chemotherapy (Tokyo) 36, Suppl. 1, 229-40. Kwan, K. C. & Till, A. E. (1973). Novel method for bioavailability assessment. Journal of Pharmaceutical Sciences 62, 1494-7. Meyers, B. R. & Wilkinson, P. (1989). Clinical pharmacokinetics of antibacterial drugs in the elderly. Implication for selection and dosage. Clinical Pharmacokinetics 17, 385-95. O'Neill, P., Nye, K., Douce, G., Andrews, J. & Wise, R. (1990). Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. Antimicrobial Agents
