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Tissue Penetration of Cefpodoxime and Cefixime in Healthy Subjects

From the Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida (P. Liu, M. Müller, H. Derendorf); Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Vienna General Hospital, Vienna University School of Medicine, Vienna, Austria (M. Müller); Department of Pharmacology, College of Medicine, University of Florida, Gainesville, Florida (M. Grant); and Sankyo Pharma GmbH, Munich, Germany (B. Obermann).

Address for reprints: Hartmut Derendorf, 1600 SW Archer Road, PO Box 100494, Gainesville, FL 32610.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (400 mg) and cefixime (400 mg) was compared using microdialysis. The results show that the total plasma concentration-time profiles of each antibiotic were similar; the area under the curve for cefpodoxime was 22.4 ± 8.7 versus 25.6 ± 8.5 mg/L•h for cefixime. However, tissue penetration was twice as high for cefpodoxime (area under the curve 15.4 ± 5.1 mg/L•h) as for cefixime (area under the curve 7.3 mg/L•h). This degree of tissue distribution is consistent with their protein binding of 21% for cefpodoxime and 65% for cefixime. After equilibration, the unbound tissue concentrations of both antibiotics were similar to their unbound plasma concentrations. Pharmacokinetic modeling was applied to describe the pharmacokinetic profiles in plasma and muscle. The study demonstrates that cefpodoxime shows greater tissue penetration than cefixime.

Key Words: Cefpodoxime • cefixime • microdialysis • tissue penetration • pharmacokinetics

Measurement of free antibiotic concentrations in the interstitial fluid at the site of the infection can be achieved by using microdialysis, which is a reliable analytical technique that permits sampling of the extracellular tissue fluid. Microdialysis has been used to investigate the in vivo pharmacokinetics of many compounds in different tissues in humans.^2,3

The tissue penetration of 2 third-generation oral cephalosporins, cefpodoxime and cefixime, into human muscle was investigated in this study using microdialysis. Both cefpodoxime and cefixime have a similar broad spectrum of antibacterial activity and are frequently used in the treatment of community-acquired respiratory tract infections. The daily dose of these 2 agents for the treatment of most respiratory tract infections is the same (400 mg), although cefixime is usually given once daily, and cefpodoxime is recommended bid. It was the goal of this study to measure the unbound concentrations of cefpodoxime and cefixime at the target site in the tissue. An extended abstract of this study was published earlier.⁴ In this article, a more detailed noncompartmental and compartmental pharmacokinetic analysis is provided.

Furthermore, the 2 compounds differ in the extent of plasma protein binding, which has been reported between 18% and 40% for cefpodoxime^5-7 compared with 65% for cefixime.⁸ Because the range of reported protein binding values for cefpodoxime is quite large, its protein binding was experimentally determined in this study.

	METHODS

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Clinical Study Design
An open, randomized, noncontrolled, 2-way crossover, single oral dose study to compare muscle penetration of cefpodoxime and cefixime by microdialysis was conducted in 6 healthy male volunteers. This study was approved by the Institutional Research Board of the University of Florida and was conducted at the General Clinical Research Center, Shands Hospital, at the University of Florida (Gainesville, Fla), in accordance with the Declaration of Helsinki (1964, with subsequent amendments). All subjects gave written informed consent prior to entry into the study.

Each subject was administered either 2 x 200 mg cefpodoxime tablets or 400 mg cefixime tablets on separate study days after routine screening examinations. Plasma and unbound muscle concentrations were monitored for 8 hours after dosing. The washout period was at least 2 weeks between drug administrations to avoid any drug carryover effect.

Blood Samples
A plastic cannula (JELCO; Johnson-Johnson, Arlington, Tex) was inserted into an antecubital vein for blood sampling. Blood samples were taken before and at 20, 40, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after dosing. The blood was collected into lithium-heparinized tubes and immediately centrifuged for 10 minutes at 3000 rpm and 4°C. The plasma samples were stored at -20°C until analyzed.

Microdialysis Samples
Microdialysis was performed as described previously.⁹ Briefly, a dialysis probe (CMA/60, membrane length: 30 mm, cutoff value: 20 KD, CMA/Microdialysis AB, Stockholm, Sweden) was inserted into a medial vastus muscle, and the microdialysis probe was then connected and perfused with Lactate Ringer's solution at a flow rate of 2 µL/min using a microinfusion pump (Harvard Apparatus 22, Holliston, Mass). In vivo individual probe recovery was determined by retrodialysis by drug, which allowed for conversion of the measured dialysate concentrations to the actual unbound muscle concentrations.¹⁰ Probe calibration was performed after a 30-minute baseline sampling period and before dosage. The dialysate was collected at 30-minute intervals before and after dosage and stored at -20°C until analyzed.

Protein Binding of Cefpodoxime
The protein binding of cefpodoxime in human plasma was determined using the ultrafiltration method. Seven different concentrations (ranging from 0.5-8 mg/L) of cefpodoxime in pooled human plasma from healthy volunteers were tested. Briefly, the plasma samples spiked with cefpodoxime were incubated at 37°C for 30 minutes, and then an aliquot of 500 µL of plasma was added into the upper part of the centrifugal filter device (Microcon, cutoff value: 30 KD, Millipore, Billerica, Mass) and centrifuged at 7000 rpm for 8 minutes. Approximately 60 to 70 µL of ultrafiltrate was collected and analyzed. The ultrafiltrate concentration represents the free plasma concentration. Triplicates were performed for each concentration.

Sample Assays
All the samples, including plasma and microdialysate as well as ultrafiltrate samples, were analyzed by validated modified high-performance liquid chromatography (HPLC) assays (C₁₈) with UV detection.^11,12 Briefly, for cefpodoxime, the mobile phase consists of 0.007M H₃PO₄ and acetonitrile (9:1), the wavelength is 254 nm, and the flow rate is 1 mL/min. Cefixime has a similar HPLC condition: the mobile phase consists of 0.007M H₃PO₄ and acetonitrile (7:1), the wavelength is 313 nm, and the flow rate is 1 mL/min. Plasma samples were precipitated with 12% perchloric acid in a 1:1 ratio and centrifuged at 8000 rpm for 3 minutes. The supernatant (20 µL) was injected into the HPLC system. Microdialysis and ultrafiltration samples (20 µL) were injected directly into the system without any preparation. The limits of quantification (LOQs) of cefpodoxime in plasma and microdialysis samples were 0.09 and 0.04 mg/L, respectively. The LOQs of cefixime in plasma and microdialysis samples were 0.3 and 0.06 mg/L, respectively.

Noncompartmental Pharmacokinetic Analysis
The following parameters were calculated for each subject, and the mean and SD of each parameter were determined.

Plasma. The terminal elimination rate constant (k_e) was calculated by linear regression of the natural logarithms of the last 4 plasma concentrations. Terminal half-life was calculated as ln(2)/k_e. The highest concentration (C_max) was obtained directly from the experimental data, together with the respective time of maximum concentration (t_max). The area under the curve (AUC) was calculated using the trapezoidal rule up to the last data point (C_x) and adding the extrapolated terminal area, calculated as C_x/k_e. The area under the first moment curve (AUMC) was calculated from a plot of C • t versus t using the trapezoidal rule up to the last data point (C_x) at time t_x and adding the extrapolated terminal area, calculated as C_x • t_x/k_e + C_x/k²_e. The mean residence time (MRT) was calculated as AUMC/AUC.

Muscle. Unbound concentrations in the extracellular muscle fluid were calculated from measured microdialysate concentrations and individual probe recovery. The parameters, such as t_1/2, C_max, t_max, AUC, AUMC, and MRT, were calculated using the same formula as for plasma samples. The tissue penetration (F) was calculated as the ratio of the unbound AUC in muscle to the total AUC in plasma (AUC_{tissue, free}/AUC_{plasma, total}).

Compartmental Pharmacokinetic Analysis
The average plasma and free tissue concentrations at each time point were fitted by nonlinear regression using the program Scientist (Version 2.0, MicroMath, Salt Lake City, Utah). The coefficient of determination (CD) and the model selection criterion (MSC) were used as criteria for the goodness of the resulting curve fits. The closer the CD is to 1, the better the agreement between measured and calculated values. The higher the MSC, the more appropriate the selected model.

Plasma. A descriptive 1-compartment body model with a mixed absorption phase and lag time was used. The equation used to describe the plasma concentration C is

(1)

where D is the dose, f is the fraction absorbed (oral bioavailability), V_d is the volume of distribution, k_a is the absorption rate constant, k_e is the elimination rate constant, t_lag is the absorption lag time, and t is time. The exponential term (1 - e^-ka^•t) was empirically added to improve the goodness of the resulting curve fits.

Muscle. Unbound muscle concentrations (C_T) were fitted simultaneously with the respective plasma concentrations. The equation used to describe the unbound tissue concentration C_T is

(2)

where f_T is the tissue distribution factor (AUC_{tissue, free}/AUC_{plasma, free}), f_u is the fraction unbound in plasma, and t_lag1 is the absorption lag time for muscle.

	RESULTS

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Protein Binding Study
The average protein binding of cefpodoxime in human plasma was 21% ± 4% (mean ± SD) (ranging from 14%-24%), with no dependence on concentration. In the previously published abstract, 25% was assumed as the average plasma protein binding of cefpodoxime and used for calculations of free plasma levels.⁴ Here, the value of 21% was used as the average protein binding of cefpodoxime in human plasma for calculations of tissue distribution factor.

Noncompartmental Pharmacokinetic Analysis
The results of the individual noncompartmental pharmacokinetic data analysis for cefpodoxime and cefixime in plasma and muscle are summarized in Table I. Parameters are presented as the mean and SD of the individual results.

The noncompartmental results of this study show that cefpodoxime and cefixime have similar plasma pharmacokinetic properties based on their AUCs and C_max (Figure 1A). However, the AUC of unbound muscle concentrations of cefpodoxime is approximately 2-fold higher than that of cefixime (15.4 mg•h/L vs 7.3 mg•h/L). Also, the C_max of cefpodoxime in the muscle was twice higher than that of cefixime (2.4 mg/L vs 0.9 mg/L) (Figure 1B). The tissue penetration factors (AUC_{tissue, free}/AUC_{plasma, total}) of cefpodoxime and cefixime were 0.70 and 0.29, respectively, which is consistent with their protein binding values.

View larger version (24K): [in this window] [in a new window]   Figure 1. Comparison of pharmacokinetic profiles of cefpodoxime (solid squares) and cefixime (solid triangles) in plasma (A) and muscle (B) in healthy male volunteers (mean + SD, n = 6) after a single oral dose of 400 mg.

Compartmental Pharmacokinetic Analysis
A 1-compartment model with mixed absorption and a lag time was able to produce good curve fits for the average total plasma and unbound muscle concentrations after oral administration of cefpodoxime tablet or cefixime tablet (Figure 2). For cefpodoxime, the CD was 0.98 and the MSC was 3.75, indicating good curve fits. For cefixime, the CD was 0.98 and the MSC was 3.41. The average lag times of cefpodoxime in the plasma and muscle were 0.43 and 0.68 hours, respectively, and the average lag times of cefixime in the plasma and muscle were 0.90 and 1.48 hours, respectively.

View larger version (30K): [in this window] [in a new window]   Figure 2. Pharmacokinetic profiles in plasma (solid squares) and muscle (open circle) in healthy male volunteers (mean + SD, n = 6) after a single oral dose of (A) 400 mg cefpodoxime and (B) 400 mg cefixime. The symbols represent the experimental data, and the lines represent the respective curve fits from nonlinear regression using simultaneous compartmental pharmacokinetics.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study provided insight into the free interstitial levels of cefpodoxime and cefixime, which are much more meaningful than currently used plasma concentrations. Using total plasma concentrations of antibiotic would overestimate the target site concentrations and probably clinical efficacy. These findings may provide an explanation for treatment failures when the causative bacterial pathogens were susceptible to antibiotics in vitro.

The study shows that it is not sufficient to only look at the plasma concentration profiles when evaluating the pharmacokinetic properties of anti-infective agents. In the case of the present study, 2 drugs with similar exposure in plasma show marked differences in their target site exposure. The main reason for this difference is the different degree of protein binding. It is well known that for beta-lactams, the time duration of the unbound drug levels above the minimum inhibitory concentration (MIC) is most relevant for the anti-infective activity.¹³ Hence, it can be expected that cefpodoxime may result in higher therapeutic efficacy in comparison with cefixime with the same dose for specific bacterial strains against which they have similar activity. The greater tissue penetration suggests favorable efficacy of cefpodoxime, which is consistent with clinical trial data.¹⁴

The most likely distribution mechanism into the muscle is diffusion driven by concentration gradients. When diffusion is completed, equal concentrations are achieved. Theoretically, the unbound tissue concentrations should be equal to the unbound plasma concentrations. In this study, unbound muscle concentrations of cefpodoxime and cefixime finally converged with their theoretical free plasma concentrations in the elimination phase. It was also found that there was a significant delay for cefixime before the drug appeared in the interstitial fluid. These results indicated that it might take some time for antibiotic tissue distribution to reach equilibrium between plasma and interstitial fluid.

Reliance on total plasma concentrations in a PK/PD approach for predicting clinical efficacy of an antibiotic is common. In vitro MIC values are routinely determined as pharmacodynamic parameters and compared with the plasma concentrations of the antibiotic without considering protein binding. However, high plasma protein binding is disadvantageous at the site of infection from a pharmacodynamic point of view. Therefore, the usage of free antibiotic tissue levels improves the accuracy of predicting clinical efficacy. Microdialysis allows for direct access to the free tissue levels. Results of this study are consistent with those of other studies and suggest that the pharmacokinetics of free antibiotic concentrations at the target site is a more appropriate pharmacokinetic input value in a PK/PD model for predicting therapeutic efficacy.^1,15-17

The results from this study, in combination with appropriate pharmacodynamic evaluation and PK/PD modeling, allow the comparison of the current dosing recommendations for these 2 compounds.¹⁸

The need for new approaches to clinical studies of antibiotics becomes evident from the present study. Refinement of dosages and dosing schedules will benefit from a PK/PD modeling approach involving free concentrations of antibiotics at target sites, especially because microdialysis now enables the accurate measurement of concentrations of free antibiotic in tissue.

	ACKNOWLEDGEMENTS

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The technical assistance of Richard Fuhrherr and General Clinical Research Center (GCRC) staff at Shands Hospital, University of Florida, is much appreciated. This work was supported by Sankyo Pharma, Germany, and in part by GCRC grant RR00082.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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15. Müller M, Stass H, Brunner M, Moller JG, Lackner E, Eichler HG. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother. 1999;43: 2345-2349.[Abstract/Free Full Text]

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