ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1992, p. 126-131 0066-4804/92/010126-06$02.00/0 Copyright (© 1992, American Society for Microbiology
Vol. 36, No. 1
Disposition of Cefpodoxime Proxetil in Healthy Volunteers and Patients with Impaired Renal Function
Received 13 June 1991/Accepted 24 October 1991
The disposition of cefpodoxime in 24 subjects with various degrees of renal function after administration of single oral dose of 200 mg of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime activity) was studied. Subjects were assigned to one of four groups (six per group): group I, normal renal function (creatinine clearance [CLCR], >90 ml/min); group II, mild renal impairment (CLCR, 50 to 80 ml/min); group III, moderate renal impairment (CLCR, 30 to 49 ml/min); or group IV, severe renal impairment (CLCR, 5 to 29 ml/min). Although cefpodoxime terminal elimination half-life in group I (2.55 0.25 h [mean standard deviation]) was not significantly different from that in group 11 (3.53 0.74 h), the half-life values for group III (5.90 1.67 h) and group IV (9.80 1.21 h) were significantly prolonged compared with those of group I. The mean absorption rate constant was similar among groups and ranged from 0.68 to 0.85 h-'. All groups exhibited absorption lag-times which were comparable (0.30 to 0.41 h), and the apparent volume of distribution was similar among groups. Cefpodoxime apparent total body clearance (CLp/F) values in groups II, III, and IV (132 29, 112 ± 41, and 55.7 9.9 ml/min, respectively) were significantly lower than that in group 1 (238 44 ml/min). Cefpodoxime CLp/F was positively correlated with CLCR (r2 = 0.79; P < 0.05): CLp/F = (1.9 CLCR) + 18.4. Renal clearance also declined with decreasing renal function. Adjustments in cefpodoxime proxetil dosage may be appropriate for patients with CLCR below 50 ml/min, depending on the infecting organism and on the site and severity of infection. Simulated plasma concentration-time data from this study suggest that 200 mg of cefpodoxime proxetil administered every 12 to 24 h to subjects with CLCR between 30 and -49 ml/min and a 200-mg dose taken every 24 h by subjects with CLCR between 5 and 29 ml/min will maintain cefpodoxime concentrations in plasma similar to those in subjects with normal renal function who receive a standard dosage of 200 mg every 12 h. a
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Cefpodoxime proxetil is an extended-spectrum cephalosporin antibiotic for oral use. Conversion of the prodrug cefpodoxime proxetil to active cefpodoxime is thought to be mediated by nonspecific intestinal brush border esterases (12, 16). Like other cephalosporins, cefpodoxime exerts antibacterial activity by binding to penicillin-binding proteins and inhibiting bacterial cell wall synthesis (27). Cefpodoxime has in vitro activity against many common grampositive and gram-negative bacteria (5, 13, 25, 26). Oral doses of 100 to 200 mg of cefpodoxime proxetil every 12 h have been shown to be effective for treating various infectious conditions involving skin and soft tissues, upper and lower respiratory tracts, and the urinary tract (6, 9, 10, 22). Single- and multiple-dose pharmacokinetic studies with cefpodoxime proxetil have revealed mean terminal elimination half-lives (t412) ranging from approximately 1.7 to 2.7 h in subjects with normal renal function (4, 10, 18, 19, 28). Results of a cefpodoxime proxetil radiolabelling study in humans indicated that virtually all the drug-related radioactivity recovered in urine can be accounted for by cefpodoxime alone (7). Cefpodoxime concentrations in serum are higher when it is administered with probenecid (20). Results of a study in which nine patients with mild to moderate renal dysfunction (creatinine clearance [CLCR], .36 ml/min) were administered 200 mg of cefpodoxime proxetil orally after a meal showed that mean t1/2 was greater than that in normal *
subjects (24). Thus, it appears that glomerular filtration and tubular secretion are active components involved in the elimination of cefpodoxime. The present study was designed to further evaluate the effect of reduced renal function on the disposition of cefpodoxime after the administration of a single, 200-mg oral dose of cefpodoxime proxetil (cefpodoxime equivalents) to patients with normal and reduced renal function. MATERIALS AND METHODS
Subjects and study design. Twenty-four nonobese subjects between the ages of 22 and 65 years participated in the study after giving written informed consent. Each participant underwent a medical history, physical examination, and laboratory evaluation prior to study participation. Individuals were grouped by renal function, on the basis of the mean of two ambulatory measured 24-h CLCR obtained within 2 weeks before study participation. Each individual CLCR value was within 20% of the patient's respective mean value. Study participants were assigned to one of four groups based on CLCR values: group I (normal renal function, CLCR > 90 ml/min), group II (mild renal impairment, CLCR of 50 to 80 ml/min), group III (moderate renal impairment, CLCR of 30 to 49 ml/min), or group IV (severe renal impairment, CLCR of 5 to 29 ml/min). None of the subjects had received known enzyme-inducing agents, theophylline, cimetidine, metoclopramide, or similar drugs within 30 days before the study. No caffeine or caffeine-containing substances were allowed
Corresponding author. 126
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JOHN V. ST. PETER,l.2* MARIE T. BORIN,3 GEORGE S. HUGHES,3 JUDY S. KELLOWAY,"2 BRUCE E. SHAPIRO,' AND CHARLES E. HALSTENSON"2 The Drug Evaluation Unit, Hennepin County Medical Center, Minneapolis, Minnesota 554151*; College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 554552; and The Upjohn Company, Kalamazoo, Michigan 49OOJ3
VOL. 36, 1992
DISPOSITION OF CEFPODOXIME PROXETIL IN RENAL FAILURE
for 24 h before or throughout the study. Similarly, all subjects refrained from alcohol 2 days prior to the study until completion. Concurrent drug therapy was permitted for subjects in groups II, III, and IV. This included medications for the treatment of hypertension, diabetes mellitus, and hyperparathyroidism. All such concurrent therapy was continued unchanged for 2 weeks before the study and during
time to achieve maximum concentration (Tmax) were determined by visual inspection of individual concentration-time profiles. The terminal elimination rate constant (kel) was estimated by linear regression of log-transformed cefpodoxime plasma concentration-time curves through the terminal linear phase, (i.e., from the 6-h postdose sample through the last measured concentration). The t112 was determined by dividing In 2 by kei. Plasma cefpodoxime area under the concentration-time curve from time 0 to infinity (AUCO-) was estimated by using the linear trapezoidal rule for time zero to the time of the last measured plasma concentration with extrapolation to infinity by adding the value of the last measured plasma concentration divided by kel. Apparent cefpodoxime clearance (CL/F) was calculated from the following equation: CLp/F = dose/AUC,, where F represents the fraction of dose which is bioavailable, and dose is the amount (in milligrams) of oral cefpodoxime proxetil (cefpodoxime equivalents) that was administered. The absorption rate constant (k) was determined by using the Wagner-Nelson method. The tag time to beginning of absorption' (tiag) was estimated by nonlinear regression analysis of the fraction absorbed (fabs) versus'time data fitted to the following relationship:
fabs = 1-e[k.(t - tiag)] where t is time. The apparent volume of distribution (V/F) was determined from the following relationship: VIF = CLp/kel Renal clearance (CLR) of cefpodoxime was calculated with the following equation: CLR = AR,, 96/AUCO96 where ARO,96 is the amount of cefpodoxime recovered in the urine from time zero to 96 h, and AUC>96 is the estimated area under the plasma concentration versus time curve during the same time interval. For purposes of simulation, compartmental analysis of the cefpodoxime concentration-time data was also completed. The most appropriate compartmental model was selected using the Akaike information criteria (1). Curves were fit to a one-compartment model assuming first-order input, firstorder output, and a lag time. Weighted (1/observed concentration) nonlinear regression analysis and PCNONLIN were used to obtain final estimates of AUCQ,. V/F, ka, k, and tiag. Statistical analysis. Group differences in age, weight, height, and pharmacokinetic parameters were investigated by analysis of variance and by using the Neuman-Keuls post hoc test for significance. Chi-square test was used to detect group differences in race or sex. The correlations between CLCR and various pharmacokinetic parameters were assessed by orthogonal regression analysis (17). Statistical significance was defined as P < 0.05. Data are expressed as the mean ± standard deviation.
RESULTS The demographics and CLCR values for the 24 study participants are summarized in Table 1. There were no significant differences in sex or race distribution, weight, or height among groups. A significant difference (P . 0.05) in age was detected between group I and group IV only.
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the study. Aluminum hydroxide-containing antacids, Shohl's solution, or calcium supplements were not taken within 4 hours before 'or after cefpodoxime proxetil administration. Dosing and sample collection. All participants were admitted to the Clinical Research Unit 12 h prior to drug administration. A standard light snack was served 10 h before dosing, after which subjects fasted until 4 hours after dosing. Each subject ingested two cefpodoxime proxetil 100-mg tablets (lot 25,267; The Upjohn Co., Kalamazoo, Mich.) with 180 ml of water. Blood samples (5 ml) were collected in lavender-top tubes (Becton-Dickson, Rutherford, N.J.) containing freeze-dried EDTA as anticoagulant immediately before dosing (zero hour) and at the following times after cefpodoxime proxetil ingestion: 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20, 24, and 36 h. Plasma was harvested from each specimen, frozen on dry ice, and stored at -70°C until assayed. Urine was collected from all subjects before cefpodoxime proxetil administration (-12 to 0 h) and during the following intervals after administration: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, 48 to 72, and 72 to 96 h. During each collection period the urine flask was stored at 4°C. Urine volumes were quantitated, and an aliquot was saved and frozen at -70°C until analysis. Analytical procedures. The concentrations of cefpodoxime in plasma and urine samples were determined by using reversed-phase high-performance liquid chromatographic methods (3, 21). Plasma samples were acidified with a phosphoric acid solution containing the internal standard (cefaclor) on a C8 Advanced Automated Sample Processor and directly chromatographed on a C18 column by using a mobile phase consisting of 0.05 M sodium acetate buffer (pH 6.0)-acetonitrile-methanol in a ratio of 92:4:4 (vol/vol/vol). The eluate was monitored with a UV detector at 254 nm, and quantitation was achieved by using peak-height ratios. The linear range for analysis of cefpodoxime in plasma was 0.012 to 5.5 ,ug/ml. The between-day coefficient of variation (CV) for calibration standards ranged from 0.8 to 16%. Intraday CVs in plasma ranged from 0.12 to 1.0%. Assay precision, measured as CV for estimated concentration of quality control samples averaged 8.0% (range, 5 to 9%) at three cefpodoxime plasma concentrations (0.1, 0.8, and 2.0 jig/ ml). Assay accuracy, expressed as the ratio of estimated'to theoretical quality control concentrations, averaged 100% (range, 99 to 105%) for low, medium, and high QC samples. Determination of cefpodoxime in urine was achieved by direct injection of filtered urine by using column switching with UV detection at 254 nm. Quantitation using peak-height response was linear over the calibration standard range of 0.10 to 50 jig/ml, with between-day CVs ranging from 0.3% to 16%. Intraday CVs ranged from 0.10 to 0.60%. Assay precision averaged 4% (range, 2.3 to 5%) for 1.0-, 9.8-, and 19.8-,ug/ml QC urine samples, and assay accuracy was 99%. The limits of quantitation for cefpodoxime in plasma and urine were 0.012 and 0.264 p.g/ml, respectively. Data analysis. Pharmacokinetic parameters were estimated by- using noncompartmental techniques. The maximum concentration in plasma of cefpodoxime (Cmax) and the
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ST. PETER ET AL.
TABLE 1. Subject demographic characteristicsa
Group' Sfexmale)
Age (yr)
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Wt (kg)
Ht (cm)
CLCR(mI/
74.8 ± 11 174 + 9.5 118 + 31 69.0 + 15 173 + 7.3 69.8 + 11 68.5 + 15 167 ± 13 37.7 + 3.2 82.6 ± 16 173 ± 10 18.2 ± 6.8
III, moderate
-
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Mean cefpodoxime plasma concentration versus time data for the four groups are illustrated in Fig. 1. Estimated noncompartmental pharmacokinetic parameters for groups I through IV are summarized in Table 2. Mean Cmax tended to increase with decreasing renal function; however, mean values were only significantly different between groups I and IV. Tmax tended to increase with decreasing renal function, but these differences were not statistically significant. Likewise, tiag and ka were similar among groups. Significant differences in t1/2 were detected among groups, with the mean t1/2 being significantly longer for groups III and IV than for groups I and II. Mean plasma cefpodoxime AUCO, increased as CLCR declined. CLp/F was significantly lower in groups II, III, and IV than in group I. Declining renal function did not appear to alter V/F in any consistent manner, but the mean value for group III was significantly greater than that for groups II and IV. A significantly lower percentage of the administered dose (fe) was recovered in the urine of groups III and IV than in the urine of groups I and II. Groups II, III, and IV also demonstrated significantly lower CLR values than group I. (One subject from group III was deleted from analysis of urinary recovery data because of incomplete collection of urine.) Cefpodoxime CLp/F and CLR were positively correlated
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a Data are presented as mean ± standard deviation. b I, normal renal function; II, mild renal impairment; impairment; IV, severe renal impairment. C Statistically significant (P < 0.05) versus group I.
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DISPOSITION OF CEFPODOXIME PROXETIL IN RENAL FAILURE
VOL. 36, 1992
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with CLCR (Fig. 2). The relationships obtained from these regressions were as follows: CLp/F = 1.90 (CLCR) + 18.40 (r2 = 0.79; P < 0.05) and CLR = 0.58 (CLCR) + 4.22 (r2 = 0.79; P < 0.05). Noncompartmental estimates were generally similar to those obtained by using compartmental techniques with the exception of t1/2 and ka in group I only. Noncompartmental estimates of t1/2 were significantly longer than compartmental estimates (2.55 ± 0.25 h versus 1.77 + 0.49 h; P < 0.05) in this group. Similarly, noncompartmental ka values were larger than compartmental estimates (0.76 ± 0.18 h-1 versus 0.56 ± 0.17 h-1; P < 0.05). In spite of these statistical differences the final estimates of t1/2 and ka were within the range of previously reported values for normal subjects with normal renal function. Simulated plasma concentration-time profiles were generated to reflect the CLCR bounds of each group. Estimated CLpJF values were obtained by applying the a priori high and low CLCR values from each group to the above regression equation. Values for tIag, V/F, and kc, were assumed to be constant between groups and were based upon the average of the mean parameter values from the four groups. On the basis of recent results, bioavailability was assumed to be 50% (23). Concentrations were normalized to a body weight of 70 kg. Steady-state plasma cefpodoxime concentration-time profiles after oral doses of 200 mg of cefpodoxime proxetil were simulated at various dose intervals for all four groups (Fig. 3). DISCUSSION
Pharmacokinetic parameter estimates obtained from subjects with normal renal function (group I) were similar to those seen in previous single- and multiple-dose cefpodoxime proxetil studies in normal subjects (4, 11). The fact that subjects in this group were younger than those in group IV should not influence the data from this study, since age alone has no effect on cefpodoxime proxetil disposition (2, 23).
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The Cmax and Tmax of cefpodoxime tended to increase with declining renal function; however, significant betweengroup differences were not detected. Whether this trend is due to changes in distribution or elimination or both cannot be determined from the data since absolute bioavailability was not estimated. However, declining elimination appears to be a probable cause given that estimates of V/F do not appear to change between groups. This study demonstrates that after oral ingestion of cefpodoxime proxetil, consistent alterations in cefpodoxime disposition occur in subjects across a wide range of CLCR values (Fig. 2). AUCO_x and t1/2 increased while CLp/F, CLR, and cefpodoxime urinary recovery declined as renal function decreased. Significant relationships between CL1JF, CLR, and CLCR were demonstrated. The significant (P < 0.05) positive y-intercept terms for these relationships are suggestive of a small nonrenal elimination component for cefpodoxime. The trends noted in cefpodoxime disposition with reduced renal function are comparable to those
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ST. PETER ET AL.
ACKNOWLEDGMENTS We gratefully acknowledge the secretarial assistance of Jan Lovick and Dorothy Wenzel and the technical assistance of the staff of the Clinical Research Unit. REFERENCES 1. Akaike, H. 1976. An information criterion (AIC). Math. Sci. 14:5-9. 2. Blackhouse, C., A. Wade, P. Williamson, D. Tremblay, and B. Lenfant. 1990. Multiple dose pharmacokinetics of cefpodoxime in young adult and elderly patients. J. Antimicrob. Chemother.
26(Suppl. E):29-34. 3. Bombardt, P. A., K. S. Cathcart, B. E. Bothwell, and S. K. Closson. 1991. Determination of cefpodoxime levels and cefpodoxime stability in human urine by direct injection HPLC with column-switching. J. Liq. Chromatogr. 14:1729-1746. 4. Borin, M. T., G. S. Hughes, C. R. Spillers, and R. K. Patel. 1990. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob. Agents Chemother. 32:443-449. 5. Fass, R. J., and V. L. Helsel. 1988. In vitro activity of U-76,252 (CS-807), a new oral cephalosporin. Antimicrob. Agents Chemother. 32:1082-1085. 6. Fujii, A., H. Maeda, H. Yamazaki, S. Arakawa, and S. Kamidono. 1988. Clinical studies on CS-807 in the urological field. Chemotherapy (Tokyo) 36(Suppl. 1):788-801. 7. Greenfield, J. C., M. T. Borin, S. J. Loux, M. T. Verburg, K. S.
Cathcart, J. E. Brewer, M. Courtney, G. S. Hughes, and V. K. Sood. 1991. Disposition of [14C]-cefpodoxime proxetil after a single oral dose to normal human volunteers, abstr. 101. 4th Int. Symp. Synthesis Appl. Isotopically Labelled Compounds, 3 to 7 September 1991, Toronto, Ontario, Canada. 8. Guay, D. R. P., R. C. Meatherall, G. K. Harding, and G. R. Brown. 1986. Pharmacokinetics of cefixime (CL 284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrob. Agents Chemother. 30:485-490. 9. Hayashi, I., and K. Ohnuma. 1988. Clinical results of CS-807 on acute exacerbation of chronic bronchitis. Chemotherapy (To-
kyo) 36(Suppl. 1):386-390.
10. Hoshino, M., S. Mogi, and H. Takahashi. 1988. Clinical evaluation of CS-807 against skin and soft tissue infections. Chemo-
therapy (Tokyo) 36(Suppl. 1):1074-1078. 11. Hughes, G. S., D. L. Heald, K. B. Barker, R. K. Patel, C. R. Spillers, K. C. Watts, D. H. Batts, and A. R. Euler. 1989. The
effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin. Pharmacol. Ther. 46:674-685. 12. Jones, R. N., and A. L. Barry. 1988. Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807). Antimicrob. Agents Chemother. 32:443-449. 13. Jones, R. N., A. L. Barry, M. Pfaller, S. D. Allen, L. W. Iyers, and P. C. Fuchs. 1988. Antimicrobial activity of U-76,252 (CS-807), a new orally administered cephalosporin ester, including recommendations for MIC quality control. Diagn. Microbiol. Infect. Dis. 9:59-63. 14. Kneer, J., Y. K. Tam, R. A. Blouin, F. J. Frey, E. Keller, C. Stathakis, B. Luginbuehl, and K. Stoeckel. 1989. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency. Antimicrob. Agents Chemother. 33:1952-1957. 15. Koeppe, P., D. Hoffler, M. Mattiucci, and E. Kienle. 1989. Pharmacokinetics in healthy volunteers and patients with impaired renal function after oral cefotiam hexetil. Acta Therapeutica 15:337-354. 16. Komai, T., K. Kawai, H. Tsubake, T. Tokui, T. Kinoshita, and M. Tanaka. 1988. Absorption, distribution, metabolism, and excretion of CS-807, a new oral cephem antibiotic, in experimental animals. Chemotherapy (Tokyo) 36(Suppl. 1):229240. 17. Morrison, D. F. 1967. Multivariate statistical methods, p. 84-85, 230-234. McGraw-Hill Book Co., New York. 18. O'Neill, P., K. Nye, G. Douce, J. Andrews, and R. Wise. 1990. Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. Antimicrob. Agents Chemother. 34:232-234. 19. Saito, A. 1987. Program Abstr. 27th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 665. 20. Sawae, Y., Y. Kumagi, T. Ishimura, K. Tagaki, Y. Niho, M. Takii, H. Shigeoka, K. Kuwahara, M. Migake, and Y. Naito. 1988. Laboratory and clinical studies on CS-807. Chemotherapy (Tokyo) 36(Suppl. 1):538-557. 21. Steenwyk, R. C., J. E. Brewer, M. E. Royer, and K. S. Cathcart. Reversed-phase liquid chromatographic determination of cefpodoxime in human plasma. J. Liq. Chromatogr., in press. 22. Takizawa, K., Y. Ino, T. Iguchi, and Y. Takeda. 1988. Antibacterial and clinical effects of a newly synthesized antibiotic, CS-807, in gynecological infections. Chemotherapy (Tokyo) 36(Suppl. 1):903-906. 23. Tremblay, D., A. Dupront, C. Ho, D. Coussediere, and B. Lenfant. 1990. Pharmacokinetics of cefpoxime in young and elderly volunteers after single doses. J. Antimicrob. Chemother. 26(Suppl. E):21-28. 24. Ueda, S., K. Hayashi, T. Okabe, 0. Yoshizumi, T. Yamashita, N. Yoshitake, S. Noda, and K. Eto. 1988. Fundamental and clinical studies on CS-807. Chemotherapy (Tokyo) 36(Suppl. 1):859867. 25. Utsui, Y., M. Inoue, and S. Mitsuhashi. 1987. In vitro and in vivo antibacterial properties of CS-807, a new oral cephalosporin. Antimicrob. Agents Chemother. 31:1085-1092.
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documented with other oral cephalosporin agents, such as cefixime, cefetamet pivoxil, and cefotiam hexetil (8, 14, 15). Cefpodoxime concentration-time simulations, with parameter estimates from this study and a normal dose of 200 mg orally every 12 h, demonstrate increasing Cmax, Tmax, and trough concentrations as CLCR declines. For subjects with CLCR of 50 to 80 ml/min, the simulations demonstrate that a 200-mg dose every 12 h maintains cefpodoxime concentrations in plasma within the range comparable to that seen in normal subjects. As CLCR falls to between 30 and 49 ml/min, dosing intervals of 12 and 24 h yield simulated cefpodoxime concentrations in plasma reflecting some accumulation with the 12-h interval and minimal or no accumulation with the 24-h interval (Fig. 3). Cefpodoxime trough levels in plasma exceeding 1 p.g/ml are achieved with the 12-h dosing interval, and trough concentrations exceeding 0.2 pLg/ml are attained with the 24-h dosing interval. For individuals with CLCR from 5 to 29 ml/min, a dose interval of 24 h provides cefpodoxime concentration-time profile with peak concentrations ranging from 3.6 to 6.6 pLg/ml and trough cefpodoxime concentrations from 0.5 to 3.1 p.g/ml with the highest peaks and troughs at a CLCR of 5 ml/min. These cefpodoxime levels in plasma exceed MICs for 90% of the strains tested for many organisms in cefpodoxime's antibacterial spectrum, and the higher trough concentrations achieved with the recommended dosing intervals may be desirable for organisms towards which the drug has higher MICs for 90% of the strains, such as Staphylococcus aureus and Staphylococcus epidermidis (4). In summary, the plasma disposition of cefpodoxime proxetil is altered in the presence of reduced renal function. Cmax and Tmax tend to increase as renal function declines. Cefpodoxime CLp/F and CLR are highly correlated with CLCR, and both decrease with declining renal function. Dosage adjustment by extension of the dosing interval for patients with CLCR below 50 ml/min may be appropriate in order to avoid excessive accumulation of the drug in plasma.
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DISPOSITION OF CEFPODOXIME PROXETIL IN RENAL FAILURE
26. Wiedemann, B., and A. Jansen. 1990. Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in-vitro model. J. Antimicrob. Chemother. 26:71-79. 27. Yakota, T., E. Suzuki, and K. Aria. 1988. Cefpodoxime proxetil, its in vitro antibacterial activity, affinity to bacterial penicillinbinding proteins, and synergy of bactericidal activity with serum
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complement and mouse-cultured macrophages. Drugs Exp. Clin. Res. 16:495-500. 28. Yamasaku, F., Y. Suzuki, and K. Uno. 1988. Pharmacokinetic study on new oxime-type oral cephems, comparison of CS-807, T-2588 and cefixime in the same subjects. Chemotherapy (Tokyo) 36(Suppl. 1):267-273.
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Vol. 36, No. 1
Disposition of Cefpodoxime Proxetil in Healthy Volunteers and Patients with Impaired Renal Function
Received 13 June 1991/Accepted 24 October 1991
The disposition of cefpodoxime in 24 subjects with various degrees of renal function after administration of single oral dose of 200 mg of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime activity) was studied. Subjects were assigned to one of four groups (six per group): group I, normal renal function (creatinine clearance [CLCR], >90 ml/min); group II, mild renal impairment (CLCR, 50 to 80 ml/min); group III, moderate renal impairment (CLCR, 30 to 49 ml/min); or group IV, severe renal impairment (CLCR, 5 to 29 ml/min). Although cefpodoxime terminal elimination half-life in group I (2.55 0.25 h [mean standard deviation]) was not significantly different from that in group 11 (3.53 0.74 h), the half-life values for group III (5.90 1.67 h) and group IV (9.80 1.21 h) were significantly prolonged compared with those of group I. The mean absorption rate constant was similar among groups and ranged from 0.68 to 0.85 h-'. All groups exhibited absorption lag-times which were comparable (0.30 to 0.41 h), and the apparent volume of distribution was similar among groups. Cefpodoxime apparent total body clearance (CLp/F) values in groups II, III, and IV (132 29, 112 ± 41, and 55.7 9.9 ml/min, respectively) were significantly lower than that in group 1 (238 44 ml/min). Cefpodoxime CLp/F was positively correlated with CLCR (r2 = 0.79; P < 0.05): CLp/F = (1.9 CLCR) + 18.4. Renal clearance also declined with decreasing renal function. Adjustments in cefpodoxime proxetil dosage may be appropriate for patients with CLCR below 50 ml/min, depending on the infecting organism and on the site and severity of infection. Simulated plasma concentration-time data from this study suggest that 200 mg of cefpodoxime proxetil administered every 12 to 24 h to subjects with CLCR between 30 and -49 ml/min and a 200-mg dose taken every 24 h by subjects with CLCR between 5 and 29 ml/min will maintain cefpodoxime concentrations in plasma similar to those in subjects with normal renal function who receive a standard dosage of 200 mg every 12 h. a
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Cefpodoxime proxetil is an extended-spectrum cephalosporin antibiotic for oral use. Conversion of the prodrug cefpodoxime proxetil to active cefpodoxime is thought to be mediated by nonspecific intestinal brush border esterases (12, 16). Like other cephalosporins, cefpodoxime exerts antibacterial activity by binding to penicillin-binding proteins and inhibiting bacterial cell wall synthesis (27). Cefpodoxime has in vitro activity against many common grampositive and gram-negative bacteria (5, 13, 25, 26). Oral doses of 100 to 200 mg of cefpodoxime proxetil every 12 h have been shown to be effective for treating various infectious conditions involving skin and soft tissues, upper and lower respiratory tracts, and the urinary tract (6, 9, 10, 22). Single- and multiple-dose pharmacokinetic studies with cefpodoxime proxetil have revealed mean terminal elimination half-lives (t412) ranging from approximately 1.7 to 2.7 h in subjects with normal renal function (4, 10, 18, 19, 28). Results of a cefpodoxime proxetil radiolabelling study in humans indicated that virtually all the drug-related radioactivity recovered in urine can be accounted for by cefpodoxime alone (7). Cefpodoxime concentrations in serum are higher when it is administered with probenecid (20). Results of a study in which nine patients with mild to moderate renal dysfunction (creatinine clearance [CLCR], .36 ml/min) were administered 200 mg of cefpodoxime proxetil orally after a meal showed that mean t1/2 was greater than that in normal *
subjects (24). Thus, it appears that glomerular filtration and tubular secretion are active components involved in the elimination of cefpodoxime. The present study was designed to further evaluate the effect of reduced renal function on the disposition of cefpodoxime after the administration of a single, 200-mg oral dose of cefpodoxime proxetil (cefpodoxime equivalents) to patients with normal and reduced renal function. MATERIALS AND METHODS
Subjects and study design. Twenty-four nonobese subjects between the ages of 22 and 65 years participated in the study after giving written informed consent. Each participant underwent a medical history, physical examination, and laboratory evaluation prior to study participation. Individuals were grouped by renal function, on the basis of the mean of two ambulatory measured 24-h CLCR obtained within 2 weeks before study participation. Each individual CLCR value was within 20% of the patient's respective mean value. Study participants were assigned to one of four groups based on CLCR values: group I (normal renal function, CLCR > 90 ml/min), group II (mild renal impairment, CLCR of 50 to 80 ml/min), group III (moderate renal impairment, CLCR of 30 to 49 ml/min), or group IV (severe renal impairment, CLCR of 5 to 29 ml/min). None of the subjects had received known enzyme-inducing agents, theophylline, cimetidine, metoclopramide, or similar drugs within 30 days before the study. No caffeine or caffeine-containing substances were allowed
Corresponding author. 126
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JOHN V. ST. PETER,l.2* MARIE T. BORIN,3 GEORGE S. HUGHES,3 JUDY S. KELLOWAY,"2 BRUCE E. SHAPIRO,' AND CHARLES E. HALSTENSON"2 The Drug Evaluation Unit, Hennepin County Medical Center, Minneapolis, Minnesota 554151*; College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 554552; and The Upjohn Company, Kalamazoo, Michigan 49OOJ3
VOL. 36, 1992
DISPOSITION OF CEFPODOXIME PROXETIL IN RENAL FAILURE
for 24 h before or throughout the study. Similarly, all subjects refrained from alcohol 2 days prior to the study until completion. Concurrent drug therapy was permitted for subjects in groups II, III, and IV. This included medications for the treatment of hypertension, diabetes mellitus, and hyperparathyroidism. All such concurrent therapy was continued unchanged for 2 weeks before the study and during
time to achieve maximum concentration (Tmax) were determined by visual inspection of individual concentration-time profiles. The terminal elimination rate constant (kel) was estimated by linear regression of log-transformed cefpodoxime plasma concentration-time curves through the terminal linear phase, (i.e., from the 6-h postdose sample through the last measured concentration). The t112 was determined by dividing In 2 by kei. Plasma cefpodoxime area under the concentration-time curve from time 0 to infinity (AUCO-) was estimated by using the linear trapezoidal rule for time zero to the time of the last measured plasma concentration with extrapolation to infinity by adding the value of the last measured plasma concentration divided by kel. Apparent cefpodoxime clearance (CL/F) was calculated from the following equation: CLp/F = dose/AUC,, where F represents the fraction of dose which is bioavailable, and dose is the amount (in milligrams) of oral cefpodoxime proxetil (cefpodoxime equivalents) that was administered. The absorption rate constant (k) was determined by using the Wagner-Nelson method. The tag time to beginning of absorption' (tiag) was estimated by nonlinear regression analysis of the fraction absorbed (fabs) versus'time data fitted to the following relationship:
fabs = 1-e[k.(t - tiag)] where t is time. The apparent volume of distribution (V/F) was determined from the following relationship: VIF = CLp/kel Renal clearance (CLR) of cefpodoxime was calculated with the following equation: CLR = AR,, 96/AUCO96 where ARO,96 is the amount of cefpodoxime recovered in the urine from time zero to 96 h, and AUC>96 is the estimated area under the plasma concentration versus time curve during the same time interval. For purposes of simulation, compartmental analysis of the cefpodoxime concentration-time data was also completed. The most appropriate compartmental model was selected using the Akaike information criteria (1). Curves were fit to a one-compartment model assuming first-order input, firstorder output, and a lag time. Weighted (1/observed concentration) nonlinear regression analysis and PCNONLIN were used to obtain final estimates of AUCQ,. V/F, ka, k, and tiag. Statistical analysis. Group differences in age, weight, height, and pharmacokinetic parameters were investigated by analysis of variance and by using the Neuman-Keuls post hoc test for significance. Chi-square test was used to detect group differences in race or sex. The correlations between CLCR and various pharmacokinetic parameters were assessed by orthogonal regression analysis (17). Statistical significance was defined as P < 0.05. Data are expressed as the mean ± standard deviation.
RESULTS The demographics and CLCR values for the 24 study participants are summarized in Table 1. There were no significant differences in sex or race distribution, weight, or height among groups. A significant difference (P . 0.05) in age was detected between group I and group IV only.
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the study. Aluminum hydroxide-containing antacids, Shohl's solution, or calcium supplements were not taken within 4 hours before 'or after cefpodoxime proxetil administration. Dosing and sample collection. All participants were admitted to the Clinical Research Unit 12 h prior to drug administration. A standard light snack was served 10 h before dosing, after which subjects fasted until 4 hours after dosing. Each subject ingested two cefpodoxime proxetil 100-mg tablets (lot 25,267; The Upjohn Co., Kalamazoo, Mich.) with 180 ml of water. Blood samples (5 ml) were collected in lavender-top tubes (Becton-Dickson, Rutherford, N.J.) containing freeze-dried EDTA as anticoagulant immediately before dosing (zero hour) and at the following times after cefpodoxime proxetil ingestion: 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16, 20, 24, and 36 h. Plasma was harvested from each specimen, frozen on dry ice, and stored at -70°C until assayed. Urine was collected from all subjects before cefpodoxime proxetil administration (-12 to 0 h) and during the following intervals after administration: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 36, 36 to 48, 48 to 72, and 72 to 96 h. During each collection period the urine flask was stored at 4°C. Urine volumes were quantitated, and an aliquot was saved and frozen at -70°C until analysis. Analytical procedures. The concentrations of cefpodoxime in plasma and urine samples were determined by using reversed-phase high-performance liquid chromatographic methods (3, 21). Plasma samples were acidified with a phosphoric acid solution containing the internal standard (cefaclor) on a C8 Advanced Automated Sample Processor and directly chromatographed on a C18 column by using a mobile phase consisting of 0.05 M sodium acetate buffer (pH 6.0)-acetonitrile-methanol in a ratio of 92:4:4 (vol/vol/vol). The eluate was monitored with a UV detector at 254 nm, and quantitation was achieved by using peak-height ratios. The linear range for analysis of cefpodoxime in plasma was 0.012 to 5.5 ,ug/ml. The between-day coefficient of variation (CV) for calibration standards ranged from 0.8 to 16%. Intraday CVs in plasma ranged from 0.12 to 1.0%. Assay precision, measured as CV for estimated concentration of quality control samples averaged 8.0% (range, 5 to 9%) at three cefpodoxime plasma concentrations (0.1, 0.8, and 2.0 jig/ ml). Assay accuracy, expressed as the ratio of estimated'to theoretical quality control concentrations, averaged 100% (range, 99 to 105%) for low, medium, and high QC samples. Determination of cefpodoxime in urine was achieved by direct injection of filtered urine by using column switching with UV detection at 254 nm. Quantitation using peak-height response was linear over the calibration standard range of 0.10 to 50 jig/ml, with between-day CVs ranging from 0.3% to 16%. Intraday CVs ranged from 0.10 to 0.60%. Assay precision averaged 4% (range, 2.3 to 5%) for 1.0-, 9.8-, and 19.8-,ug/ml QC urine samples, and assay accuracy was 99%. The limits of quantitation for cefpodoxime in plasma and urine were 0.012 and 0.264 p.g/ml, respectively. Data analysis. Pharmacokinetic parameters were estimated by- using noncompartmental techniques. The maximum concentration in plasma of cefpodoxime (Cmax) and the
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ST. PETER ET AL.
TABLE 1. Subject demographic characteristicsa
Group' Sfexmale)
Age (yr)
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Wt (kg)
Ht (cm)
CLCR(mI/
74.8 ± 11 174 + 9.5 118 + 31 69.0 + 15 173 + 7.3 69.8 + 11 68.5 + 15 167 ± 13 37.7 + 3.2 82.6 ± 16 173 ± 10 18.2 ± 6.8
III, moderate
-
renal
Mean cefpodoxime plasma concentration versus time data for the four groups are illustrated in Fig. 1. Estimated noncompartmental pharmacokinetic parameters for groups I through IV are summarized in Table 2. Mean Cmax tended to increase with decreasing renal function; however, mean values were only significantly different between groups I and IV. Tmax tended to increase with decreasing renal function, but these differences were not statistically significant. Likewise, tiag and ka were similar among groups. Significant differences in t1/2 were detected among groups, with the mean t1/2 being significantly longer for groups III and IV than for groups I and II. Mean plasma cefpodoxime AUCO, increased as CLCR declined. CLp/F was significantly lower in groups II, III, and IV than in group I. Declining renal function did not appear to alter V/F in any consistent manner, but the mean value for group III was significantly greater than that for groups II and IV. A significantly lower percentage of the administered dose (fe) was recovered in the urine of groups III and IV than in the urine of groups I and II. Groups II, III, and IV also demonstrated significantly lower CLR values than group I. (One subject from group III was deleted from analysis of urinary recovery data because of incomplete collection of urine.) Cefpodoxime CLp/F and CLR were positively correlated
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DISPOSITION OF CEFPODOXIME PROXETIL IN RENAL FAILURE
VOL. 36, 1992
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with CLCR (Fig. 2). The relationships obtained from these regressions were as follows: CLp/F = 1.90 (CLCR) + 18.40 (r2 = 0.79; P < 0.05) and CLR = 0.58 (CLCR) + 4.22 (r2 = 0.79; P < 0.05). Noncompartmental estimates were generally similar to those obtained by using compartmental techniques with the exception of t1/2 and ka in group I only. Noncompartmental estimates of t1/2 were significantly longer than compartmental estimates (2.55 ± 0.25 h versus 1.77 + 0.49 h; P < 0.05) in this group. Similarly, noncompartmental ka values were larger than compartmental estimates (0.76 ± 0.18 h-1 versus 0.56 ± 0.17 h-1; P < 0.05). In spite of these statistical differences the final estimates of t1/2 and ka were within the range of previously reported values for normal subjects with normal renal function. Simulated plasma concentration-time profiles were generated to reflect the CLCR bounds of each group. Estimated CLpJF values were obtained by applying the a priori high and low CLCR values from each group to the above regression equation. Values for tIag, V/F, and kc, were assumed to be constant between groups and were based upon the average of the mean parameter values from the four groups. On the basis of recent results, bioavailability was assumed to be 50% (23). Concentrations were normalized to a body weight of 70 kg. Steady-state plasma cefpodoxime concentration-time profiles after oral doses of 200 mg of cefpodoxime proxetil were simulated at various dose intervals for all four groups (Fig. 3). DISCUSSION
Pharmacokinetic parameter estimates obtained from subjects with normal renal function (group I) were similar to those seen in previous single- and multiple-dose cefpodoxime proxetil studies in normal subjects (4, 11). The fact that subjects in this group were younger than those in group IV should not influence the data from this study, since age alone has no effect on cefpodoxime proxetil disposition (2, 23).
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The Cmax and Tmax of cefpodoxime tended to increase with declining renal function; however, significant betweengroup differences were not detected. Whether this trend is due to changes in distribution or elimination or both cannot be determined from the data since absolute bioavailability was not estimated. However, declining elimination appears to be a probable cause given that estimates of V/F do not appear to change between groups. This study demonstrates that after oral ingestion of cefpodoxime proxetil, consistent alterations in cefpodoxime disposition occur in subjects across a wide range of CLCR values (Fig. 2). AUCO_x and t1/2 increased while CLp/F, CLR, and cefpodoxime urinary recovery declined as renal function decreased. Significant relationships between CL1JF, CLR, and CLCR were demonstrated. The significant (P < 0.05) positive y-intercept terms for these relationships are suggestive of a small nonrenal elimination component for cefpodoxime. The trends noted in cefpodoxime disposition with reduced renal function are comparable to those
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ST. PETER ET AL.
ACKNOWLEDGMENTS We gratefully acknowledge the secretarial assistance of Jan Lovick and Dorothy Wenzel and the technical assistance of the staff of the Clinical Research Unit. REFERENCES 1. Akaike, H. 1976. An information criterion (AIC). Math. Sci. 14:5-9. 2. Blackhouse, C., A. Wade, P. Williamson, D. Tremblay, and B. Lenfant. 1990. Multiple dose pharmacokinetics of cefpodoxime in young adult and elderly patients. J. Antimicrob. Chemother.
26(Suppl. E):29-34. 3. Bombardt, P. A., K. S. Cathcart, B. E. Bothwell, and S. K. Closson. 1991. Determination of cefpodoxime levels and cefpodoxime stability in human urine by direct injection HPLC with column-switching. J. Liq. Chromatogr. 14:1729-1746. 4. Borin, M. T., G. S. Hughes, C. R. Spillers, and R. K. Patel. 1990. Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil. Antimicrob. Agents Chemother. 32:443-449. 5. Fass, R. J., and V. L. Helsel. 1988. In vitro activity of U-76,252 (CS-807), a new oral cephalosporin. Antimicrob. Agents Chemother. 32:1082-1085. 6. Fujii, A., H. Maeda, H. Yamazaki, S. Arakawa, and S. Kamidono. 1988. Clinical studies on CS-807 in the urological field. Chemotherapy (Tokyo) 36(Suppl. 1):788-801. 7. Greenfield, J. C., M. T. Borin, S. J. Loux, M. T. Verburg, K. S.
Cathcart, J. E. Brewer, M. Courtney, G. S. Hughes, and V. K. Sood. 1991. Disposition of [14C]-cefpodoxime proxetil after a single oral dose to normal human volunteers, abstr. 101. 4th Int. Symp. Synthesis Appl. Isotopically Labelled Compounds, 3 to 7 September 1991, Toronto, Ontario, Canada. 8. Guay, D. R. P., R. C. Meatherall, G. K. Harding, and G. R. Brown. 1986. Pharmacokinetics of cefixime (CL 284,635; FK 027) in healthy subjects and patients with renal insufficiency. Antimicrob. Agents Chemother. 30:485-490. 9. Hayashi, I., and K. Ohnuma. 1988. Clinical results of CS-807 on acute exacerbation of chronic bronchitis. Chemotherapy (To-
kyo) 36(Suppl. 1):386-390.
10. Hoshino, M., S. Mogi, and H. Takahashi. 1988. Clinical evaluation of CS-807 against skin and soft tissue infections. Chemo-
therapy (Tokyo) 36(Suppl. 1):1074-1078. 11. Hughes, G. S., D. L. Heald, K. B. Barker, R. K. Patel, C. R. Spillers, K. C. Watts, D. H. Batts, and A. R. Euler. 1989. The
effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil. Clin. Pharmacol. Ther. 46:674-685. 12. Jones, R. N., and A. L. Barry. 1988. Antimicrobial activity and disk diffusion susceptibility testing of U-76,253A (R-3746), the active metabolite of the new cephalosporin ester, U-76,252 (CS-807). Antimicrob. Agents Chemother. 32:443-449. 13. Jones, R. N., A. L. Barry, M. Pfaller, S. D. Allen, L. W. Iyers, and P. C. Fuchs. 1988. Antimicrobial activity of U-76,252 (CS-807), a new orally administered cephalosporin ester, including recommendations for MIC quality control. Diagn. Microbiol. Infect. Dis. 9:59-63. 14. Kneer, J., Y. K. Tam, R. A. Blouin, F. J. Frey, E. Keller, C. Stathakis, B. Luginbuehl, and K. Stoeckel. 1989. Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency. Antimicrob. Agents Chemother. 33:1952-1957. 15. Koeppe, P., D. Hoffler, M. Mattiucci, and E. Kienle. 1989. Pharmacokinetics in healthy volunteers and patients with impaired renal function after oral cefotiam hexetil. Acta Therapeutica 15:337-354. 16. Komai, T., K. Kawai, H. Tsubake, T. Tokui, T. Kinoshita, and M. Tanaka. 1988. Absorption, distribution, metabolism, and excretion of CS-807, a new oral cephem antibiotic, in experimental animals. Chemotherapy (Tokyo) 36(Suppl. 1):229240. 17. Morrison, D. F. 1967. Multivariate statistical methods, p. 84-85, 230-234. McGraw-Hill Book Co., New York. 18. O'Neill, P., K. Nye, G. Douce, J. Andrews, and R. Wise. 1990. Pharmacokinetics and inflammatory fluid penetration of cefpodoxime proxetil in volunteers. Antimicrob. Agents Chemother. 34:232-234. 19. Saito, A. 1987. Program Abstr. 27th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 665. 20. Sawae, Y., Y. Kumagi, T. Ishimura, K. Tagaki, Y. Niho, M. Takii, H. Shigeoka, K. Kuwahara, M. Migake, and Y. Naito. 1988. Laboratory and clinical studies on CS-807. Chemotherapy (Tokyo) 36(Suppl. 1):538-557. 21. Steenwyk, R. C., J. E. Brewer, M. E. Royer, and K. S. Cathcart. Reversed-phase liquid chromatographic determination of cefpodoxime in human plasma. J. Liq. Chromatogr., in press. 22. Takizawa, K., Y. Ino, T. Iguchi, and Y. Takeda. 1988. Antibacterial and clinical effects of a newly synthesized antibiotic, CS-807, in gynecological infections. Chemotherapy (Tokyo) 36(Suppl. 1):903-906. 23. Tremblay, D., A. Dupront, C. Ho, D. Coussediere, and B. Lenfant. 1990. Pharmacokinetics of cefpoxime in young and elderly volunteers after single doses. J. Antimicrob. Chemother. 26(Suppl. E):21-28. 24. Ueda, S., K. Hayashi, T. Okabe, 0. Yoshizumi, T. Yamashita, N. Yoshitake, S. Noda, and K. Eto. 1988. Fundamental and clinical studies on CS-807. Chemotherapy (Tokyo) 36(Suppl. 1):859867. 25. Utsui, Y., M. Inoue, and S. Mitsuhashi. 1987. In vitro and in vivo antibacterial properties of CS-807, a new oral cephalosporin. Antimicrob. Agents Chemother. 31:1085-1092.
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documented with other oral cephalosporin agents, such as cefixime, cefetamet pivoxil, and cefotiam hexetil (8, 14, 15). Cefpodoxime concentration-time simulations, with parameter estimates from this study and a normal dose of 200 mg orally every 12 h, demonstrate increasing Cmax, Tmax, and trough concentrations as CLCR declines. For subjects with CLCR of 50 to 80 ml/min, the simulations demonstrate that a 200-mg dose every 12 h maintains cefpodoxime concentrations in plasma within the range comparable to that seen in normal subjects. As CLCR falls to between 30 and 49 ml/min, dosing intervals of 12 and 24 h yield simulated cefpodoxime concentrations in plasma reflecting some accumulation with the 12-h interval and minimal or no accumulation with the 24-h interval (Fig. 3). Cefpodoxime trough levels in plasma exceeding 1 p.g/ml are achieved with the 12-h dosing interval, and trough concentrations exceeding 0.2 pLg/ml are attained with the 24-h dosing interval. For individuals with CLCR from 5 to 29 ml/min, a dose interval of 24 h provides cefpodoxime concentration-time profile with peak concentrations ranging from 3.6 to 6.6 pLg/ml and trough cefpodoxime concentrations from 0.5 to 3.1 p.g/ml with the highest peaks and troughs at a CLCR of 5 ml/min. These cefpodoxime levels in plasma exceed MICs for 90% of the strains tested for many organisms in cefpodoxime's antibacterial spectrum, and the higher trough concentrations achieved with the recommended dosing intervals may be desirable for organisms towards which the drug has higher MICs for 90% of the strains, such as Staphylococcus aureus and Staphylococcus epidermidis (4). In summary, the plasma disposition of cefpodoxime proxetil is altered in the presence of reduced renal function. Cmax and Tmax tend to increase as renal function declines. Cefpodoxime CLp/F and CLR are highly correlated with CLCR, and both decrease with declining renal function. Dosage adjustment by extension of the dosing interval for patients with CLCR below 50 ml/min may be appropriate in order to avoid excessive accumulation of the drug in plasma.
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26. Wiedemann, B., and A. Jansen. 1990. Antibacterial activity of cefpodoxime proxetil in a pharmacokinetic in-vitro model. J. Antimicrob. Chemother. 26:71-79. 27. Yakota, T., E. Suzuki, and K. Aria. 1988. Cefpodoxime proxetil, its in vitro antibacterial activity, affinity to bacterial penicillinbinding proteins, and synergy of bactericidal activity with serum
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complement and mouse-cultured macrophages. Drugs Exp. Clin. Res. 16:495-500. 28. Yamasaku, F., Y. Suzuki, and K. Uno. 1988. Pharmacokinetic study on new oxime-type oral cephems, comparison of CS-807, T-2588 and cefixime in the same subjects. Chemotherapy (Tokyo) 36(Suppl. 1):267-273.
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