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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Clinical Pharmacology Research Center, Department of Adult and Pediatric Medicine, Bassett Healthcare, Cooperstown, New York.
Address for reprints: Guy W. Amsden, PharmD, FCP, Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Levofloxacin • pharmacokinetics • bioequivalence • drug interactions
With the exception of norfloxacin, the fluoroquinolones are labeled as being able to be administered with or without food due to research conducted with the standard Food and Drug Administration (FDA)-mandated drug-food bioequivalence study meal of a high-fat, high-calorie, low-mineral breakfast.1 Other studies have demonstrated that the bioavailability of these same agents is significantly altered when they are coadministered with antacids, drugs, and supplements that are laden with multivalent ions such as calcium, iron, and zinc.2,3 Although in regulatory terms, these two issues are separate, the rising prevalence of foods being fortified with these same minerals makes them appear less so.4 As an example, a study by Neuhofel et al5 demonstrated a significant interaction between ciprofloxacin and calcium-fortified orange juice. Since ciprofloxacin is prescribed twice daily, the investigators theorized that most patients would take their first dose in the morning with breakfast (i.e., taking it with the juice) and the second dose near their evening meal. Study results demonstrated that when taken with 12 ounces of calcium-fortified orange juice, the AUC of a dose of ciprofloxacin decreased by 38%, and the Cmax decreased by 41% as compared to when it was taken with an equivalent amount of water.5 Although not to the same extent, more recent studies of similar design demonstrated that levofloxacin and gatifloxacin also lacked bioequivalence when coadministered with calcium-fortified orange juice.6,7 As quinolones are concentration-dependent and/or exposure-dependent killing antimicrobials, decreases in the Cmax and/or AUC have the potential to cause treatment failure and resistance development due to their pharmacokinetic and pharmacodynamic outcome predictors (Cmax:MIC, AUC:MIC) no longer being optimized.8,9
As only a component of a potential breakfast meal has been studied to date to characterize the existence of an interaction, the current study using levofloxacin was conducted with a full breakfast to characterize whether the degree of the interaction varies with the amount of minerals consumed. Rather than use the standard FDA breakfast, the most commonly consumed breakfast food of 2002, ready-to-eat cereal, was served in conjunction with the previously used calcium-fortified orange juice to simulate a standard American breakfast.1,10 To test for a correlation between mineral consumption and degree of interaction, subjects were allowed to measure their own portions of each of the breakfast food components.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Each subject received the following dosage regimens in random order: (1) a single 500-mg tablet of levofloxacin (Levaquin®, Ortho-McNeil Corporation, lots 91P0550/92P0264E, expirations 04/04:02/05) with 12 ounces of water; (2) a single 500-mg tablet of levofloxacin with subject-chosen portions of calcium-fortified orange juice (Minute MaidTM Premium Calcium Original), ready-to-eat cereal (General Mills, Whole Grain TotalTM), and skim milk as a cereal diluent; and (3) a single 500-mg tablet of levofloxacin with subject-chosen portions of calcium-fortified orange juice (Minute MaidTM Premium Calcium Original), ready-to-eat cereal (General Mills, Whole Grain TotalTM), and water/nothing as a cereal diluent. During the first study arm that a subject received the meal, portions of the juice, cereal, and milk/water were measured so that the same amounts could be eaten during their second fed study arm. All subjects fasted for at least 8 hours prior to dosing and did not consume anything but ad libitum amounts of water for the subsequent 4 hours. Caffeine, alcohol, and smoking were prohibited throughout the study. Each dosing regimen was separated by at least a 7-day washout period.
Blood samples were collected immediately prior to drug administration (baseline) and then at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, and 48 hours after drug administration. Plasma was harvested from the whole-blood samples and stored at -80°C until assayed. All plasma specimens were shipped frozen on dry ice to Emprexe Analytical, LLC (Buffalo, NY) for analysis of levofloxacin concentrations. A previously described reverse-phase, high-pressure liquid chromatographic (HPLC) assay was validated and used to quantitate levofloxacin in heparinized human plasma samples using difloxacin as the internal standard.7 Linearity was observed over the calibration curve range of 0.100 to 10.0 µg/mL, and the assay had a limit of detection of 14.7 ng/mL (signal-to-noise ratio [S/N] = 5) for levofloxacin in plasma. The overall precision (percentage relative standard deviation [% RSD]) and accuracy (percentage analytical recovery [% AR]) of the assay were 3.66% (0.38%-5.25%) and 100% (98.9%-102%), respectively.
Levofloxacin plasma concentration versus time data were analyzed using the
TopFit 2.0 program and noncompartmental pharmacokinetic methods.
Pharmacokinetic parameters that were derived included time to peak plasma
concentration (tmax), peak plasma concentration (Cmax),
terminal elimination half-life (t1/2), total oral clearance (CL/F,
with F denoting bioavailability), apparent volume of distribution during the
terminal phase (Vz/F), area under the plasma concentration-time curve from
time 0 to 24 hours (AUC24), and AUC from time 0 to infinity
(AUC
). Statistical analysis of the data was performed using
SigmaStat version 2.03 and SYSTAT version 7.0 (SPSS, Inc., Chicago, IL).
Descriptive statistics were completed for each pharmacokinetic parameter for
each of the three study arms as well as for subject demographics and mineral
intake. All data were normally distributed and log-transformed.
Pharmacokinetic parameters were compared using a one-way repeated-measures
analysis of variance (ANOVA) with the Bonferroni t-test for all
pairwise multiple-comparison procedures. A statistically significant
difference was determined to occur if p 
0.05. In addition, to
determine if there was a food effect on bioavailability between the test and
control phases, the 90% confidence intervals (CI) for the ratio of the
population geometric means between test and control phases for
Cmax, tmax, AUC, and AUC24,
based on log-transformed data, were calculated. A food effect on
bioavailability was determined to be present if the 90% CI was not contained
within the equivalence limits of 80% to 125% for AUC,
AUC24,orCmax.1
Presence of correlations between total mineral intake (ratio of sum of
consumed milligram amounts of calcium, iron, and zinc to the sum of one
serving size of each food's [1 cup each juice and milk,
34 cup
cereal] milligram amounts of calcium, iron, and zinc) to the ratio of the
population geometric means for the two fed arms versus the control fasting arm
for all three bioequivalence parameters was conducted using Pearson product
measure correlation tests. If any correlations were discovered, they then
underwent linear regression analysis to try to establish any predictive
relationship equation. Power calculations indicated that to detect a 20%
difference in AUC24 of a single dose of 500 mg levofloxacin, a
sample size of 14 subjects would have 70% power to detect it.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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On average, subjects consumed 1.28 (range: 0.67-1.67) portions of juice,
0.52 (range: 0.13-1.16) portions of milk, and 1.16 (range: 0.33-2.87) portions
of cereal. Translated into mineral intake, when subjects had levofloxacin
given with the meal without milk, they took it with 1607 (range: 592-3348) mg
of calcium, 21 (range: 6-52) mg of iron, and 17 (range: 5-43) mg of zinc (mean
total mineral equivalent = 0.975 [range: 0.36-2.04]) on average. When given
with the milk-containing breakfast, they took levofloxacin with 1771 (range:
721-3607) mg of calcium, 22 (range: 6-52) mg of iron, and 18 (range: 5-44) mg
of zinc (mean total mineral equivalent = 1.07 [range: 0.43-2.20]) on average.
As demonstrated in Table I (see
also Figure 1), this
coadministration led to a significant increase in tmax (46% with
milk, 57% without milk) and significant decreases in Cmax (24% with
milk, 23% without milk) and both AUC24 (16% with milk, 15% without
milk) and AUC (16% with milk, 14% without milk). Values for
both Vz/F and CL/F also significantly increased with food coadministration but
to similar degrees, as evidenced by the lack of significant change in
t1/2. Although the 90% CIs for the ratio of the geometric means
between the water (control) and fed arms noted no effect on AUC24
(with milk, 83.4% [80.2%, 86.7%]; without milk, 84.7% [80.4%, 89.1%]) or
AUC (with milk, 83.8% [80.0%, 87.6%]; without milk, 85.9%
[80.7%, 91.2%]), when tested for an effect on bioequivalence, there was an
effect on Cmax for both fed arms (with milk, 79.2% [72.6%, 85.7%];
without milk, 79.1% [73.3%, 84.9%]). Although no confidence interval range is
set for tmax values, the same calculations noted an effect (with
milk, 108.3% [83.7%, 132.8%]; without milk, 197.6% [145.5%, 249.7%]) if one
were to reference the guidelines for Cmax and
AUC24/AUC. When the various pharmacokinetic
parameters for both fed arms were compared to consumed mineral equivalents,
the only combination that demonstrated a significant correlation (correlation
coefficient = -0.606, p = 0.0217) was the subjects' mineral
equivalents and AUC24 for the with-milk meal. When this correlation
underwent linear regression analysis, the beginnings of a predictive
relationship between the amount of mineral intake and 24-hour drug exposure
were established (see Figure
2).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Three studies preceding the current one have examined the impact of nondairy, mineral-fortified foods on the bioequivalence of fluoroquinolones, which are well known to have negative interactions with substances containing large amounts of multivalent ions.2-4 The studies to date have investigated the impact that calcium-fortified orange juice has on the pharmacokinetics and bioequivalence of ciprofloxacin, gatifloxacin, and levofloxacin, using water and nonfortified orange juice as controls.5-7 The first study demonstrated that 12 ounces of calcium-fortified orange juice decreased the Cmax and AUC of a single 500-mg oral dose of ciprofloxacin by 41% and 38%, respectively.5 This was in stark contrast to the changes for the two parameters with the nonfortified juice, which were only about half of those seen with the fortified version. As a result, not only was there a lack of bioequivalence (Westlake criteria)11,12 when ciprofloxacin was administered with the calcium-fortified juice as compared to when it was taken with water, but there was also a lack of bioequivalence when the fortified juice arm was compared to the nonfortified juice arm. The lack of bioequivalence between the two juice arms indicated that the calcium (525 mg) that the juice was fortified with caused the interaction.5 The second study also demonstrated a lack of bioequivalence (90% CIs for the ratio of geometric means of Cmax, 91.4% [76.6%, 106.2%]) when gatifloxacin was coadministered with 12 ounces of calcium-fortified orange juice, although the change in Cmax was not statistically significant (3.7 vs. 3.2 mg/L, 13.5% change). Like the first study, changes in pharmacokinetic parameters with the nonfortified juice were 50% to 67% smaller than those demonstrated with the fortified juice and did not reach significance in terms of bioequivalence.6 The third study also demonstrated a lack of bioequivalence when levofloxacin was coadministered with calcium-fortified orange juice (Cmax, 89.0% [78.1%, 99.8%]), with the amount of change in Cmax both exceeding that seen with gatifloxacin, and when levofloxacin was studied with the FDA proscribed breakfast (18% vs. 13.5% vs. 14%, respectively).6,7,13
As orange juice, fortified or not, is usually only one component of a breakfast, a common breakfast ready-to-eat cereal was studied in the current investigation, along with or without milk as a cereal diluent to rule out any overriding dairy effect. In addition to using a common breakfast combination, subjects were allowed to pour their own portions of each food to make the study results reflective of the variability in portion sizes chosen from person to person and, by association, the amount of variability that would be demonstrated in an interaction between the minerals in the foods and levofloxacin. This variability not only provides a sense of reality to the results but also allows for analyses to be conducted to try to identify a correlation between the amount of mineral fortification and the amount of interaction. As the results demonstrated, all the goals of the study were attained. Not only did the combination of foods provide a greater decrease in Cmax (33% greater) and AUC24 (97% greater) than that previously demonstrated when levofloxacin was administered just with the fortified juice, but the average Cmax also decreased 71% more than that demonstrated when levofloxacin was administered with the FDA breakfast.7,13 The lack of bioequivalence in this study was again due to the changes in Cmax rather than AUC, which decreased to a lesser extent than Cmax (16% vs. 24%). The smaller change in combination with the increase in tmax, again as in past studies, argues that the type of interaction demonstrated may be a combination of reversible and irreversible interactions between the multivalent ions and levofloxacin, such as adsorption and chelation, respectively. However, due to the limited matrix sampling, it is impossible to rule out that competition for absorption sites between components of the foods and levofloxacin may have also played a part in the interaction.7,14,15
Although the correlation is weak at this time due to the number of data points involved, the results suggest that with enough data from additional studies, a stronger correlation can be developed that may allow pharmaceutical companies to calculate the amount of fortification that their compounds may be able to be exposed to prior to losing bioequivalence. Identifying this can be crucial with drugs such as antibiotics since significant decreases in peak concentrations or systemic exposures can result in suboptimal clinical and bacteriologic outcomes in patients as well as pathogen resistance development.16 Although it can be argued that this study is less meaningful than a study examining the concentrations or exposures achieved during a full course of therapy, the fact that data exist demonstrating that rapid antibiotic administration after presentation to a physician results in a shorter length of stay suggests that the first dose is a crucial one.17 Because of this, data concerning a single dose with an antibiotic may actually be more relevant than a drug from another class of drugs.
In conclusion, this study demonstrates a lack of bioequivalence when levofloxacin is coadministered with a commonly consumed breakfast as opposed to when it is administered in a fasting state. The extent of the interaction exceeds that previously demonstrated with the standard FDA breakfast and provides a correlation between the amount of interaction and mineral content that may, in the future, allow for an equation to be more fully developed that would be capable of predicting how much fortification can be consumed before bioequivalence is lost.
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FOOTNOTES |
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Submitted for publication March 15, 2003; Revised version accepted June 15, 2003.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Food and Drug Administration: Food-Effect Bioavailability and Fed Bioequivalence Studies: Study Design, Data Analysis, and Labeling. Draft Guidance for Industry. Bethesda, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, 2001.
2. Nix DE, Watson WA, Lener M, Frost RW, Krol G, Goldstein H, et al: Effects of aluminum and magnesium antacids and ranitidine on the absorption of ciprofloxacin. Clin Pharmacol Ther 1989;46: 700-705.[Web of Science][Medline] [Order article via Infotrieve]
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12. Westlake WJ: Bioavailability and bioequivalence of pharmaceutical formulations, in: Westlake WJ (ed.), Biopharmaceutical Statistics for Drug Development. New York: Marcel Dekker, 1988; 329-352.
13. Levaquin product information, Ortho-McNeil, 2002.
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et al: Polymethoxylated flavones in orange juice are inhibitors of
P-glycoprotein but not cytochrome P450 3A4. J Pharmacol Exper
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17. Battleman DS, Callahan M, Thaler HT: Rapid antibiotic delivery and
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