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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Depomed Inc, Menlo Park, California (Dr Washington, Dr Hou, Dr Berner), Biovail Contract Research, Toronto, Ontario, Canada (Dr Campanella and Dr Hughes) and the Clinical Microbiology Institute, Wilsonville, Oregon (Dr Brown).
Address for reprints: Bret Berner, PhD, Depomed, Inc., 1360 O'Brien Drive, Menlo Park, CA 94025-1436.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Bioavailability • urinary excretion • minimum inhibitory concentrations
The 2 studies reported here compare the pharmacokinetics and pharmacodynamics of ciprofloxacin ER tablets with conventional ciprofloxacin IR tablets. Ciprofloxacin shows reduced bioavailability from the colon, and consequently, conventional extended-release formulations of ciprofloxacin are either of short duration, such as the currently marketed extended-release tablet that releases all of its drug in 1.5 to 2 hours, or exhibit reduced bioavailability. The ciprofloxacin ER tablet used in these studies delivers approximately 90% of the 500 mg dose to the upper gastrointestinal (GI) tract, where ciprofloxacin is best absorbed,4 within 6 hours of dosing. The extended-release profile of ciprofloxacin ER is designed to provide the peak levels of ciprofloxacin that are required to avoid resistance5 while extending the rate of delivery and providing reduced concentrations of ciprofloxacin in the lower GI tract. This extended release is accomplished by a combination of polymeric swelling and dissolution that maintains the size of the tablet such that it is retained in the fed stomach as the meal is digested, thus providing sustained delivery of ciprofloxacin to the upper GI tract throughout a 6-hour interval and allows for comparable bioavailability to the IR product.
The objective of this study was to measure the plasma and urinary pharmacokinetics of once-daily ciprofloxacin ER and twice-daily ciprofloxacin IR and to determine the ratios of plasma and urinary ciprofloxacin concentrations and pharmacokinetic parameters to the ciprofloxacin minimum inhibitory concentrations (MICs) for bacterial strains commonly associated with uncomplicated UTIs. The pharmacodynamic properties of fluoroquinolones have been well described.6-9 Fluoroquinolones exhibit concentration-dependent bactericidal activity and the ratios of the peak plasma drug concentration (Cmax) to MICs and the area under the concentration-time curve (AUC) to MIC are important markers of pharmacodynamic activity that are useful for optimizing therapy and predicting outcomes.10 For UTIs, the concentration of antibiotic in the urine and the urine concentration to MIC ratio are also important for predicting efficacy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Study Design and Drug Administration
The study protocols and informed consent forms were approved by the Institutional Review Board of Biovail Contract Research (Toronto, Ontario, Canada), and the studies were conducted by Biovail Contract Research in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines. Both studies were randomized, open-label, 2-way crossover studies, with a 7-day washout period between treatments. Subjects received ciprofloxacin ER (Proquin XR, Depomed Inc, Menlo Park, Calif) 500 mg once daily and ciprofloxacin IR (CIPRO, Bayer Pharmaceuticals, West Haven, Conn) 250 mg twice daily (every 12 hours) for either 1 day (single-dose study) or 3 days (steady-state study). In both studies, ciprofloxacin ER and ciprofloxacin IR were administered immediately after dinner, and the second daily dose of ciprofloxacin IR was given after breakfast. Meals were in accordance with the guidelines for food effect studies (1000 calories, 50% fat).
Blood and Urine Sample Collection
In the single-dose study, blood samples were collected before dosing and at specified times through 36 hours after dosing. Urine samples were collected before dosing through 36 hours after dosing and were pooled at specified intervals. In the steady-state study, blood samples were collected before dosing on days 1, 2, and 3, and at specified times up to 24 hours after the final dose. Urine samples were collected throughout the study and were pooled at specified intervals from before dosing on day 1 to 24 hours after the final dose. Blood samples were kept in an ice bath before centrifugation and centrifuged as soon as possible under refrigerated conditions at 3500 rpm for 7 minutes. The plasma was transferred to appropriately labeled tubes and frozen at –70°C until assayed. A minimum of 10 mL of each pooled urine sample was transferred to labeled containers and stored at –70°C until assay.
Analytical Methodology
Plasma samples were analyzed for ciprofloxacin using a validated high performance liquid chromatography (HPLC) method with fluorescence detection. Ciprofloxacin and the internal standard, norfloxacin, were extracted from acidified plasma using polymer-based solid phase extraction cartridges and were eluted with acidified methanol. Chromatography was performed using a C18,3.5 µm, 75 x 4.6-mm Zorbax SB column (Agilent Technologies, Palo Alto, Calif), with the mobile phase consisting of acetonitrile: 0.02 M potassium dihydrogen phosphate (pH 3.0) (10:90, v/v) at a flow rate of 2 mL/min. A fluorescence detector (Waters 474, Waters Corp, Milford, Mass) was used with an excitation wavelength of 278 nm and an emission wavelength of 456 nm. The lower limit of quantitation was approximately 25 ng/mL.
Urine samples were analyzed for ciprofloxacin and the ciprofloxacin metabolites (desethyleneciprofloxacin [M1], sulfociprofloxacin [M2], oxociprofloxacin [M3], and formylciprofloxacin [M4]) using a validated HPLC method with UV detection. Ciprofloxacin, M1, M2, M3, M4, and the internal standard, norfloxacin, were extracted from urine using polymer-based solid phase extraction cartridges and were eluted in 2 steps, first with methanol and then with acidified methanol. Chromatography was performed under the same conditions as used for plasma samples except that the flow rate was 1 mL/min and detection was performed using a UV detector (
= 280 nm). The lower limits of quantitation were approximately 1.5 µg/mL for urinary ciprofloxacin and 0.5 µg/mL for urinary ciprofloxacin metabolites.
Minimum Inhibitory Concentrations
Ciprofloxacin MICs were determined for 3 American Type Culture Collection (ATCC) quality control strains (Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, and Staphylococcus aureus ATCC 29213) and for 5 clinical strains isolated within the previous 1 to 2 years (Ecoli N9688, Klebsiella pneumoniae N9189, E faecalis ST12,296, Staphylococcus saprophyticus SP8822, and Proteus mirabilis N9287). The MICs were determined in vitro as a function of pH for each bacterial strain using a standard microdilution susceptibility testing procedure.11
Pharmacokinetic Analysis
Plasma pharmacokinetic parameters were calculated using noncompartmental methods (SAS version 8.0, SAS Institute, Cary, NC). For the single-dose study, Cmax, time to maximum concentration (Tmax), AUC from time zero to infinity (AUC0-inf), and half-life (t
) were determined. In the steady-state study, Cmax, minimum concentration (Cmin), average concentration (Cavg), Tmax, AUC throughout a dosing interval (AUC
), and degree of fluctuation were calculated. Urinary ciprofloxacin pharmacokinetic parameters were calculated using noncompartmental methods (WinNonlin version 4.0.1, Pharsight Corp, Mountain View, Calif). For both studies, maximum excretion rate (max rate), time to maximum excretion rate (Tmaxrate), amount excreted in urine (Ae), percentage of dose excreted (%dose), and renal clearance (Clr) were determined for ciprofloxacin. For ciprofloxacin metabolites, Ae and %dose were also calculated. Arithmetic means and standard deviations (SD) or geometric means and coefficients of variation were calculated for all parameters. Because all concentrations were below the limit of quantitation, M4 data were not analyzed.
Pharmacodynamic Analysis
The ratios of mean plasma pharmacokinetic parameters (AUC, Cmax, and Cavg) to ciprofloxacin MIC values were calculated for each subject using MIC values at pH 7.3 for each bacterial strain. For urinary ciprofloxacin concentrations, the pH of each urine sample was measured and the pH-adjusted MIC was determined for each sample from a fitted MIC versus pH function for each bacterial strain. For urinary pharmacokinetic parameters (Ae and mean hourly excretion rate during 24 hours [Ae24]), the mean urinary pH was calculated for each subject and treatment and the pH-adjusted MIC was determined from the fitted MIC versus pH function for each bacterial strain. Data from the clinical isolate of E. faecalis were excluded from calculations because this organism was resistant to ciprofloxacin (MIC90 =>32 µg/mL).
Statistical Analysis
In the single-dose study, analyses of variance (ANOVAs) were performed on ln-transformed AUC and Cmax and on untransformed Tmax, t, Ae, Clr, %dose, max rate, and Tmax rate. In the steady-state study, ANOVAs were performedonln-transformedciprofloxacinAUC,Cmax, and Cmin, and untransformed Tmax,Cavg, degree of fluctuation, Ae, Clr, %dose, max rate, and Tmaxrate. The ANOVAs included treatment, period, sequence, and subjects within sequence as factors and were performed using SAS GLM procedures (SAS Institute). The relative ratios of the geometric means and the 90% confidence intervals were calculated based on the pairwise comparison of ln-transformed data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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after ciprofloxacin ER administration were 93.8% and 97.7%, respectively, of the ciprofloxacin IR values, demonstrating equivalent systemic exposure for the 2 treatments with both single doses and steady-state dosing. In the single-dose study, t was similar for ciprofloxacin ER and ciprofloxacin IR. In the steady-state study, Cmin was lower after ciprofloxacin ER administration (P < .0001), but the degree of fluctuation and mean plasma concentrations were similar for the 2 treatments.
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Urinary ciprofloxacin concentrations showed extended excretion of ciprofloxacin after ciprofloxacin ER administration compared to ciprofloxacin IR administration in both the single-dose and steady-state studies. The mean Tmaxrate after ciprofloxacin ER was 7 to 8 hours, which was significantly longer than the 3 to 4 hours after the first or second daily dose of ciprofloxacin IR (P < .0001) (Table II). For both studies, the mean max rate with ciprofloxacin ER was significantly greater than the mean max rate after the first daily dose of ciprofloxacin IR (max rate1) (P < .001) but slightly lower than or similar to that after the second daily dose of ciprofloxacin IR (max rate2)(P = .046 and P = .450 for the single-dose and steady-state studies, respectively). Mean Ae and %dose excreted in the urine were lower after ciprofloxacin ER than with ciprofloxacin IR for both the single-dose study (P = .042) and on day 3 of the steady-state study (P = .0003). Clr were similar for the 2 treatments in the single-dose study but lower with ciprofloxacin ER in the steady-state study (P = .0002). The percentages of M1, M2, and M3 metabolites recovered in the urine were similar for the 2 treatments after both single doses and steady-state dosing (M1: 0.6% and 0.6%; M2: 2.6% and 2.9%; M3: 3.3% and 3.6% for ciprofloxacin ER and ciprofloxacin IR, respectively, on day 3 of the steady-state study).
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Pharmacokinetic/Pharmacodynamic Relationships
Mean Cmax/MIC values and AUC/MIC values for the 7 susceptible uropathogens were comparable for both treatments in both studies. Mean Cavg values exceeded the MICs for the more susceptible uropathogens (both E coli species, K pneumoniae,and P mirabilis) but not for the less susceptible organisms (Saureus, S saphrophyticus, and E faecalis). The ratios of plasma pharmacokinetic parameters to MIC values were very similar for the 2 treatments in both studies for all 7 susceptible bacterial strains. Data for the steady-state study are shown in Table III; similar results were observed in the single-dose study. There was considerable intersubject variation in plasma ciprofloxacin concentrations with both treatments in both studies. The time for plasma ciprofloxacin concentrations to reach MIC levels for the more susceptible organisms in individual subjects ranged from 0.5 to 3.5 hours for ciprofloxacin ER–treated subjects and from 0.5 to 2 hours for ciprofloxacin IR–treated subjects.
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In both studies, mean urinary ciprofloxacin concentrations exceeded the MICs of the susceptible organisms at all time points for both treatments. Data for the steady-state study are shown in Figure 2; similar results were observed in the single-dose study. There was considerable intersubject variation in urinary ciprofloxacin concentrations. However, all subjects had urinary ciprofloxacin concentrations that exceeded the MICs of the susceptible organisms at all time points in both studies, except for 15 subjects in the ciprofloxacin ER group and 9 subjects in the ciprofloxacin IR group who had concentrations below the limit of quantitation (1.5 µg/mL) during the first postdose collection interval (0-2 hours) in the single-dose study.
The total urinary excretion of ciprofloxacin substantially exceeded the pH-adjusted MICs for the susceptible organisms with both treatments. The mean hourly excretion rates of ciprofloxacin were approximately 4 to 165 times greater than the MICs of the tested uropathogens in the single-dose study and approximately 4 to 209 times greater than the MICs in the steady-state study. Mean Ae/MIC and Ae24/MIC ratios with ciprofloxacin ER treatment were similar to or slightly greater than with ciprofloxacin IR treatment for all 7 susceptible uropathogens. Data for the steady-state study are shown in Figure 3; similar results were observed in the single-dose study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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The results of this study illustrate the unique pharmacokinetic properties of ciprofloxacin ER, with exended release of ciprofloxacin as shown by a significantly longer time to Cmax compared with ciprofloxacin IR. The Cmax after ciprofloxacin ER was approximately equal to the mean of the 2 peak concentrations from twice-daily dosing with ciprofloxacin IR, and systemic exposure to ciprofloxacin was very similar after ciprofloxacin ER and ciprofloxacin IR administration. The urinary pharmacokinetic profile of ciprofloxacin ER showed a similar pattern, with longer times to max rate after ciprofloxacin ER dosing. Maximum urinary excretion rates with once-daily ciprofloxacin ER were slightly greater than the mean of the 2 maximum excretion rates with twice-daily ciprofloxacin IR.
Fluoroquinolones exhibit concentration-dependent bactericidal activity. As observed elsewhere,15,16 there was considerable intersubject variation in plasma ciprofloxacin concentrations after both treatments. However, the mean plasma ciprofloxacin concentrations were greater than the MICs for the more susceptible uropathogens, although not for the less susceptible organisms. Cmax/MIC and AUC/MIC ratios are also important markers of pharmacodynamic activity that are useful for optimizing therapy and predicting outcomes.10 AUC/MIC ratios have been shown to be highly predictive of microbiological and clinical outcomes in patients with pneumonia,17 and the Cmax/MIC ratio also appears to correlate well with drug efficacy.18,19 In this study, the ciprofloxacin AUC, Cmax, and Cavg values substantially exceeded the MICs for the more susceptible uropathogens associated with uncomplicated UTIs and were similar for ciprofloxacin ER and ciprofloxacin IR after both single doses and steady-state dosing for all uropathogens tested.
For UTIs, the urinary concentration/MIC ratio and bactericidal titers may be more relevant than Cmax/MIC or AUC/MIC ratios. Bactericidal studies with ciprofloxacin and other quinolones have shown that MICs are usually greater in urine than in standard test media, most likely because of low urinary pH.20,21 Ciprofloxacin is more soluble at acidic pH, and consequently, this lower thermodynamic activity decreases bactericidal activity. Thus, the potential bactericidal activity of ciprofloxacin in urine must be based on MICs at the pH of the individual urine samples, as there is considerable intrasubject and intersubject variation in urinary pH.
As expected, there was considerable intersubject variation in urinary ciprofloxacin concentrations in this study, but the individual concentrations exceeded the pH-adjusted MICs for all strains tested at all time points, except for some subjects during the first collection period in the single-dose study. Although the percentage of ciprofloxacin dose excreted in the urine after ciprofloxacin ER was slightly lower than with ciprofloxacin IR, the mean urinary concentrations of ciprofloxacin after ciprofloxacin ER administration in both studies substantially exceeded the MICs for the susceptible uropathogens at all time points. Using pH-adjusted MIC values, the Ae/AUC and Ae24/AUC ratios with ciprofloxacin ER were similar to or slightly greater than those observed with ciprofloxacin IR, demonstrating that ciprofloxacin ER is a suitable agent for the eradication of urinary pathogens.
Ciprofloxacin ER is intended to be administered with food, although the type or amount of food is not important, and there are no safety concerns if the drug is taken under fasting conditions. When administered without food, the ciprofloxacin Cmax, AUC, and Ae values are approximately 45%, 39%, and 44%, respectively, of those obtained under fed conditions (manufacturer's data). Although the reduced urinary concentrations under fasting conditions still substantially exceed the MICs for common uropathogens, they may not be as effective for less susceptible organisms.
The clinical significance of these findings has been demonstrated in a recent, large-scale clinical study in female patients with acute, uncomplicated UTIs. The results of this study showed that once-daily administration of ciprofloxacin ER 500 mg for 3 days resulted in high uropathogen eradication and clinical cure rates (93.4% and 85.7%, respectively, at 4-11 days post-treatment) that were not inferior to twice-daily ciprofloxacin IR 250 mg for 3 days.22 In addition, ciprofloxacin ER was associated with a significantly reduced incidence of nausea and diarrhea compared to ciprofloxacin IR.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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