Effect of Calcium Carbonate on Bioavailability of Orally Administered Gemifloxacin

We investigated the effect of calcium carbonate on the oralbioavailability of gemifloxacin. Gemifloxacin was administeredalone, 2 h before, simultaneously, or 2 h after calcium carbonatein 16 volunteers. Data for 320 mg of gemifloxacin alone wereas follows: maximum concentration of drug in serum (C_max),13µg/ml; half-life, 7.33 h; and area under the concentration-timecurve from 0 h to infinity (AUC), 6.79 µg · h/ml.Only simultaneous coadministration of calcium carbonate reducedC_max (-17%) and AUC (-21%) significantly.

INTRODUCTION

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Introduction

Gemifloxacin is a new fluoroquinolone with a broad spectrumactivity against gram-positive and gram-negative bacteria. Inparticular, it has improved activity against streptococci (3)and Haemophilus influenzae (2). Therefore, it is consideredto be a potent agent for the treatment of acute exacerbationof chronic bronchitis (7).

Calcium is the most common drug for prophylaxis of osteoporosis,often administered in chronic bronchitis patients receivingsteroid medication. Thus, it is likely that gemifloxacin andcalcium will be coadministered. The purpose of this study wasto assess the effect of calcium coadministration on the absorptionof gemifloxacin.

MATERIALS AND METHODS

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Materials and Methods

Volunteers. Sixteen healthy Caucasian volunteers (10 males and 6 females;mean age ± standard deviation, 30 ± 7.2 years;mean body weight ± standard deviation, 71.8 ±11.3 kg; mean creatinine clearance ± standard deviation,117 ± 11 ml/min/1.73 m²) participated in the study. Thestudy was approved by the local ethics committee according toGerman law. Informed written consent was obtained from all subjects.

Study design. According to the four-way crossover design, each volunteer receivedthe following drug combinations in a random order: (A) gemifloxacinalone, (B) gemifloxacin 2 h after calcium, (C) gemifloxacinsimultaneously with calcium, and (D) gemifloxacin administered2 h before calcium. All drugs were administered orally. Thefour dosing sessions were separated by washout periods of atleast 6 days. Gemifloxacin was given after an overnight fastas a single oral dose of 320 mg (SB-265805). Calcium was administeredas one effervescent calcium carbonate tablet containing 1,000mg of calcium (Calcium Sandoz Fortissimum) dissolved in 200ml of water.

Sample collection and processing. Blood samples (5 ml) were taken before drug administration andthen at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 h afterdosing. Plasma samples were obtained by centrifugation. Urinewas collected predose and during the following periods: 0 to6, 6 to 12, 12 to 24, and 24 to 48 h postdose. The volume ofurine was measured after each collection interval, and a 5-mlaliquot of well-mixed urine was saved.

High-pressure liquid chromatography-mass spectrometry. Plasma samples were analyzed following protein precipitationwith acetonitrile. The urine samples were prepared for analysisby dilution and analyzed by high-pressure liquid chromatographyand mass spectrometry, using positive-ion spray ionization.The lower limits of quantification for each of the assays forgemifloxacin in plasma and urine were each 0.01 µg/mlusing a 50-µl aliquot. The intra-assay and interassaycoefficients of variation for determination of plasma and urinewere less than 10%.

Pharmacokinetic calculations. Plasma concentration data were analyzed by standard noncompartmentalmethods using the software program WinNonlin-Professional Edition(version 2.1). The primary pharmacokinetic parameters to determinethe effect of calcium carbonate on the bioavailability of gemifloxacinwere the maximal concentration in plasma (C_max) and the areaunder the plasma concentration-time curve extrapolated to infinity(AUC).

Primary parameters were log_e-transformed and compared by analysisof variance using the factor sequence, subject nested withinsequence, period, and regimen. The point estimates and adjusted95% confidence intervals for the difference between the regimens(B-A, C-A, and D-A) were constructed using the residual variancefrom the model, and the appropriate adjustments were made forthe three multiple comparisons using Dunnett's procedure (4).The overall significance level was maintained at 5%. The pointand interval estimates on the log scale were then back-transformedto obtain the estimates of the ratios (B:A, C:A, and D:A). Withinsubject coefficient of variation for AUC and C_max were calculatedbased on the log_e-normal distribution.

RESULTS

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Results

Pharmacokinetics. (i) Plasma. The mean plasma concentration-time profiles for gemifloxacinafter administration of a 320-mg single dose either alone orat various times relative to calcium carbonate are shown inFig. 1. Table 1 summarizes the gemifloxacin pharmacokineticsin the presence and absence of calcium carbonate. Table 2 presentsthe results of the statistical comparisons between the referenceregimen A and the test regimens B, C, and D. Simultaneous coadministrationof calcium carbonate with 320 mg of gemifloxacin significantlyreduced the C_max by 21%, and the AUC by 17%, compared to gemifloxacinalone (P < 0.05).

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FIG. 1. Arithmetic means of measured plasma concentration of gemifloxacin after administration of 320 mg of gemifloxacin alone (regimen A) and 2 h after 1,000 mg of calcium carbonate (regimen B), simultaneously with calcium carbonate (regimen C), and 2 h before calcium carbonate (regimen D) in 16 healthy volunteers. The direction of the error bars (standard deviation) is upwards for regimens A and D and downwards for regimens B and C.

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TABLE 1. Gemifloxacin pharmacokinetic parameters^a

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TABLE 2. Comparison between regimens for gemifloxacin pharmacokinetic parameters^a

(ii) Urine. The extent of urinary excretion (Table 1) of gemifloxacin wasnot notably different when gemifloxacin was given 2 h beforeor after calcium, although there was a slight, not significantdecrease when calcium was given simultaneously. There were noclear differences in renal clearance between treatments.

Safety and tolerance. The volunteers' overall tolerance to gemifloxacin was good.No severe adverse events (AE) occurred. The most frequentlyreported AE was diarrhea; however there was no clear correlationbetween time of AE onset and gemifloxacin and calcium dosing,although diarrhea was only reported during the coadministrationsessions of dosing. There were no clinically significant changesin electrocardiogram parameters, blood pressure or pulse. Similarly,there were no clinically important findings in hematology, clinicalchemistry or urinalysis following dosing gemifloxacin aloneor in combination with calcium.

DISCUSSION

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Discussion

Drugs containing the multivalent cations magnesium, aluminum,and calcium have been shown to substantially interfere withthe absorption of quinolones, resulting in lower plasma concentrations(1). This interaction has been attributed to the chelation bythe multivalent cation to the quinolone and has been shown tobe a class effect, although the interaction varies across differentquinolones (6).

In the present study, simultaneously administration of calciumcarbonate with 320 mg of gemifloxacin resulted in a modest reductionin bioavailibility of gemifloxacin (average decrease of 21%for AUC and 17% for C_max). In contrast, administration of calciumcarbonate either 2 h before or after dosing with 320 mg of gemifloxacinresulted only in a minor decrease of gemifloxacin bioavailability(average decrease of 7% for the 2 h before and 5% when gemifloxacinwas administered 2 h after), compared to that observed withgemifloxacin given alone. Neither time to C_max nor the half-lifeof gemifloxacin were notably affected by coadministration ofcalcium.

The modest reduction in gemifloxacin bioavailability seen whencalcium carbonate was simultaneously administered is consistentwith that seen with other quinolones but is notably less thanseen for ofloxacin (5). Although the decrease in AUC and C_maxis considered not to be of great clinical importance, it shouldbe known and it should be explained to the patient when gemifloxacinis prescribed.

Conclusions. The results of this study demonstrate that simultaneous coadministrationof 1000 mg calcium carbonate reduces the bioavailibility ofgemifloxacin. C_max is reduced by 21% and AUC is decreased by17%. Administration of calcium either 2 h before or 2 h afteradministration of 320 mg of gemifloxacin has no relevant effecton the bioavailability of gemifloxacin. The effect of calciumcarbonate is attributed to the chelation of the multivalentcation to the quinolone gemifloxacin.

ACKNOWLEDGMENTS

The expert technical assistance of M. Rau, G. Schreiber, E.Bygate, A. Lewis, O. Dewit, E. Doyle, and D. McDonnell is gratefullyacknowledged.

This investigation was supported by a grant from GlaxoSmithKline,Greenford, Middlesex, United Kingdom.

FOOTNOTES

* Corresponding author. Mailing address: Department of Chest and Infectious Diseases, Zentralklinik E. v. Behring/Dept. Lungenklinik Heckeskorn (Academic Teaching Hospital of FU Berlin), Zum Heckeshorn 33, 14109 Berlin. Phone: 49 30 80022222. Fax: 49 30 80022623. E-mail: haloheck{at}zedat.fu-berlin.de.

REFERENCES

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