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Published ahead of print on October 3, 2007
Clin J Am Soc Nephrol 2: 1235-1240, 2007
© 2007 American Society of Nephrology
doi: 10.2215/CJN.01580407
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Mineral Metabolism and Bone Disease

Effects of Lanthanum Carbonate on the Absorption and Oral Bioavailability of Ciprofloxacin

Priscilla P. How*, James H. Fischer*, Jose A. Arruda{dagger}, and Alan H. Lau*

Departments of * Pharmacy Practice and {dagger} Medicine (Section of Nephrology), University of Illinois at Chicago, Chicago, Illinois

Correspondence: Dr. Alan H. Lau, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Room 164 (M/C 886), Chicago, IL 60612. Phone: 312-996-0894; Fax: 312-996-0379; E-mail: alanlau{at}uic.edu


   Abstract
Top
 Abstract
Introduction
 Concise Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Background and objectives: Phosphate binders such as calcium salts or sevelamer, a cationic polymer, can markedly reduce absorption of oral ciprofloxacin. This randomized, open-label, two-way, crossover study examined the influence of the cation lanthanum on systemic ciprofloxacin exposure after oral administration.

Design, setting, participants, & measurements: Twelve patients randomly received in a crossover manner a single oral dose of ciprofloxacin 750 mg alone and plus lanthanum carbonate 1 g three times daily with meals for six doses, with a washout interval of 7 to 14 d. Serial blood and urine samples were collected for 24 h after ciprofloxacin administration, and ciprofloxacin concentrations were determined using reverse-phase HPLC. Pharmacokinetic parameters of ciprofloxacin were calculated by noncompartmental methods, and the effect of lanthanum on ciprofloxacin pharmacokinetic parameters was assessed using ANOVA.

Results: Lanthanum decreased (P < 0.001) the mean ciprofloxacin area under the plasma concentration–time curve by 54% and the maximum plasma concentration by 56%. The 24-h urinary recovery of ciprofloxacin was reduced by 52% by lanthanum (P < 0.001). No statistically significant differences in ciprofloxacin time to maximum plasma concentration, elimination half-life, and renal clearance occurred between the two arms.

Conclusions: Lanthanum carbonate significantly reduces the systemic exposure to orally administered ciprofloxacin. Concomitant administration of both drugs should be avoided to prevent possible suboptimal response to ciprofloxacin.


   Introduction
Top
 Abstract
 Introduction
Concise Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 
Hyperphosphatemia is common in patients with chronic kidney disease (CKD) because of their impaired renal phosphorus excretion, resulting in secondary hyperparathyroidism and renal osteodystrophy. Patients who have stage 5 CKD and undergo hemodialysis are also more susceptible to bacterial infections and are therefore at risk for increased morbidity and mortality (1). Broad-spectrum fluoroquinolone antimicrobial agents, such as ciprofloxacin, may be used in these patients because they are commonly prescribed for the treatment of infections caused by Gram-positive and -negative microorganisms, including Pseudomonas aeruginosa.

The absorption and oral bioavailability of ciprofloxacin are affected by calcium-, magnesium-, and aluminum-containing salts (2–4). When administered concomitantly, chelate complexes are formed between the metal cations and ciprofloxacin, resulting in reduced bioavailability of the quinolone (5). Phosphate binders such as calcium carbonate, calcium acetate, and sevelamer, a cationic polymer, have also been demonstrated to decrease the absorption and oral bioavailability of ciprofloxacin (4,6).

Lanthanum carbonate is a recently available phosphate binding agent that is effective for the management of hyperphosphatemia and in preventing secondary hyperparathyroidism (7–10). Lanthanum is a naturally occurring rare earth element that shares some similar chemical properties as aluminum. Upon administration of lanthanum carbonate, lanthanum ions are released in the upper gastrointestinal tract and reduce the absorption of dietary phosphorus and may also bind to other drugs that are concomitantly administered, thereby reducing their bioavailability. However, there is limited information regarding such drug interactions with lanthanum carbonate. This study was therefore conducted to determine whether a significant pharmacokinetic interaction exists between lanthanum carbonate and ciprofloxacin.


   Concise Methods
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 Abstract
 Introduction
 Concise Methods
Results
 Discussion
 Conclusions
 Disclosures
 References
 
Study Participants
Men and women who were at least 18 yr of age, in good health as determined by medical history and laboratory testing, and within 15% of their ideal body weight (11) were eligible for enrollment. Women of child-bearing potential were eligible for participation provided that they had a negative urine pregnancy test and were using an effective means of contraception or abstaining from sexual activity. Individuals were excluded from study participation when they had a known allergy to fluoroquinolone antibiotics, history of dysphagia, or swallowing disorders or gastrointestinal condition that may interfere with absorption of the study drugs or were taking medications that might interact with ciprofloxacin or lanthanum carbonate. The study was approved by the institutional review board at the University of Illinois at Chicago. Participants provided written informed consent before the initiation of any study procedures.

Study Design
This was an open-label, two-way, crossover study. The order of each treatment arm was randomly assigned, with a washout interval of 7 to 14 d between arms. All participants abstained from alcohol and caffeine-containing food or beverages during the study. They were also instructed not to take any new medications from 1 wk before the study until after study completion.

In study arm A, participants received a single oral dose of ciprofloxacin 750 mg (Cipro; Bayer Corp., West Haven, CT). In arm B, lanthanum carbonate was administered with ciprofloxacin. For simulation of the clinical use of the drug, lanthanum carbonate 1000-mg chewable tablet (Fosrenol; Shire US Inc., Wayne, PA) was administered orally three times a day with meals for 2 consecutive days. On the second day of lanthanum carbonate administration, a single dose of ciprofloxacin 750 mg was administered immediately after the morning dose of lanthanum carbonate. Participants received a standardized breakfast that consisted of two slices of bread with butter and grape jam on all study visit days. Participants fasted for at least 8 h before ciprofloxacin administration, but no restrictions were placed on the amount of drinking water. The same lots of ciprofloxacin and lanthanum carbonate doses were used throughout the study. The participants were also asked to fill out a questionnaire to report any adverse effects at the end of each study visit.

Blood and Urine Sampling
An indwelling peripheral venous catheter was placed for serial blood sampling and was kept patent with normal saline flush. Blood samples, approximately 6 ml each, were collected from the participants at the following times: Immediately before ciprofloxacin administration and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after ciprofloxacin ingestion. The blood samples were collected in Vacutainer tubes that contained heparin (BD Vacutainer, Becton, Dickinson and Company, Franklin Lakes, NJ). After collection, the blood samples were centrifuged at 1000 x g for 10 min within 1 h of collection. The plasma was then separated, transferred into cryovials, and stored at –20°C until assayed.

The participants emptied their bladder before the start of the study, and urine was collected at the following time intervals: 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h after ciprofloxacin administration. The total urine volume was recorded, and a 5-ml aliquot from each collection period was stored at –20°C until analysis.

Sample Analysis
Plasma concentrations of ciprofloxacin were quantified by HPLC according to the method reported by Granneman and Varga (12). The assay was linear from the range of 0.0088 to 5.45 µg/ml of ciprofloxacin in plasma and from the range of 0.104 to 20.8 µg/ml of ciprofloxacin in urine. The minimum quantifiable concentration of ciprofloxacin was 0.0088 µg/ml in plasma and 0.104 µg/ml in urine. The interday coefficient of variation for replicate samples (n = 7) varied from 1.6 to 2.2% within the concentration range of the plasma standard curve and from 1.1 to 1.4% within the concentration range of the urine standard curve.

Pharmacokinetic Analysis
Plasma concentration versus time data for ciprofloxacin were analyzed by noncompartmental methods using WinNonlin version 4.1 (Pharsight Corp., Mountain View, CA). Maximum plasma concentration (Cmax) and time of maximum plasma concentration (Tmax) were obtained directly from the observed ciprofloxacin plasma concentration curves. When two maximal values were observed, the first was designated as Tmax. The terminal elimination rate constant (k) was estimated by log-linear regression of the terminal exponential portion of the plasma concentration–time curves based on at least three time points. The elimination half-life (t1/2) was determined by dividing 0.693 by k. The area under the plasma concentration time curve from time 0 to infinity (AUC0 to {infty}) was calculated from time 0 to the last measurable serum concentration (AUC0 to t) by the trapezoid rule (linear trapezoidal up to Cmax and log trapezoidal from Cmax to the last measurable plasma concentration), with extrapolation to infinity by dividing the last observed concentration by k.

The amount of unchanged ciprofloxacin excreted in the urine during 24 h (mg) was determined from the sum of the products of urine volume and ciprofloxacin concentration for each collection interval during the 24 h after ciprofloxacin administration. The fraction of the dose excreted as ciprofloxacin in the urine was calculated by dividing the amount of unchanged ciprofloxacin excreted in the urine during 24 h by 750 mg. Renal clearance (Clrenal) of ciprofloxacin was calculated by dividing the amount of ciprofloxacin excreted in the urine during 24 h by the ciprofloxacin AUC from time 0 to 24 h.

Statistical Analyses
Assuming an interindividual coefficient variation of 15 to 25% for AUC0 to {infty}, a sample size of 11 to 15 was estimated to provide at least 80% power to detect a 25% difference in AUC0 to {infty} between study arms using a two-sided test and {alpha} of 0.05. The pharmacokinetic values for each treatment are expressed as the geometric mean and coefficient of variation, with the exception of Tmax, which is expressed as the median and range. An ANOVA for repeated measures was performed to assess differences with and without lanthanum co-administration for ciprofloxacin Cmax, AUC0 to {infty}, t1/2, Clrenal, and fraction of the dose excreted in the urine as ciprofloxacin. The parameters were logarithmically (natural) transformed for the ANOVA. The ANOVA model included sequence, period, and treatment as fixed effects and subject within sequence as a random effect. The 90% confidence intervals (CI) were calculated for the difference between the ciprofloxacin plus lanthanum and ciprofloxacin alone treatment means. The anti-logs of the differences between treatment means and upper and lower confidence limits were then obtained to provide for each parameter the ratio of the geometric means and 90% CI for the ratio. The lack of a clinically significant interaction was concluded when the 90% CI for the ratios were within the equivalence limits of 80 to 125%, as recommended by the US Food and Drug Administration guidelines on bioequivalence (13). The difference in Tmax values between treatments was compared using the Wilcoxon signed rank test. Nonparametric 90% CI were constructed around the median difference in Tmax between treatments. Pharmacokinetic and statistical analyses were performed using WinNonlin version 4.1.


   Results
Top
 Abstract
 Introduction
 Concise Methods
 Results
Discussion
 Conclusions
 Disclosures
 References
 
A total of 14 healthy individuals consented to participate in the study. Two withdrew consent because of nausea and vomiting (one participant) and difficulty in placing the peripheral venous catheter (one participant); therefore, 12 participants (six men, six women; aged 26 to 50 yr) completed the study. Of these, seven were white, four were Asian, and one was Hispanic. Their mean (range) weight and height were 72.1 kg (53 to 93 kg) and 172.8 cm (155 to 193 cm), respectively. None of the participants was a smoker. Medications taken by the participants included inhaled albuterol, montelukast, desloratadine, glucosamine, atorvastatin, and oral contraceptives, none of which has documented drug interaction with the study medications. The concurrent drugs and dosages remained the same throughout the study period.

Figure 1 shows the mean ± SE ciprofloxacin plasma concentration–time curves with and without concurrent lanthanum treatment. The parameters describing the pharmacokinetics of ciprofloxacin in each study arm are presented in Table 1. Co-administration of lanthanum significantly (P < 0.001) decreased the ciprofloxacin Cmax by 56% and the AUC0 to {infty} by 54%. Correspondingly, the fraction of the dose recovered as ciprofloxacin in the urine during 24 h declined by 52% with lanthanum administration. The 90% CI of the geometric mean ratios [(ciprofloxacin + lanthanum)/ciprofloxacin alone] for Cmax, AUC0 to {infty}, and fraction recovered in urine as ciprofloxacin fell below the lower equivalent limits of 0.80 (13). The Tmax, t1/2, and Clrenal for ciprofloxacin were similar (P > 0.05) in the absence or presence of lanthanum, with the 90% CI for the geometric mean ratios of t1/2 and Clrenal falling within the no interaction limits of 0.8 to 1.25.


Figure 1
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  		Figure 1. Plasma concentration (mean ± SE) versus time curves for ciprofloxacin when administered alone and with lanthanum carbonate.

 

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  		Table 1. Summary of ciprofloxacin pharmacokinetic parameters after administration of ciprofloxacin alone and ciprofloxacin with lanthanum carbonatea

 
Figure 2 shows the individual changes in AUC0 to {infty} between treatment arms. The AUC0 to {infty} decreased in all participants when lanthanum was co-administered. The decline among individuals ranged from 6 to 73%. Figure 3 shows the fraction of ciprofloxacin dose recovered in the urine during 24 h for the individual participants.


Figure 2
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  		Figure 2. Comparison of the area under plasma concentration–time curves from time 0 to infinity (AUC0 to {infty}) between the two arms for individual participants (dotted lines). The solid line represents the mean AUC0 to {infty} for all participants.

 

Figure 3
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  		Figure 3. Comparison of fraction of ciprofloxacin dose recovered in the urine during 24 h between the two arms for individual participants (dotted lines). The solid line represents the mean fraction recovered for all participants.

 
Both study medications were generally well tolerated. Two participants experienced headache when ciprofloxacin was administered alone; the remaining participants did not report any adverse events. When ciprofloxacin was co-administered with lanthanum carbonate, all participants but one reported experiencing at least one adverse effect. Nausea was most commonly experienced, followed by abdominal pain, bloating, headache, and dizziness. None of the adverse effects was severe enough in nature to require discontinuation from the study.


   Discussion
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
Conclusions
 Disclosures
 References
 
Ciprofloxacin, a broad-spectrum fluoroquinolone antibiotic that is bactericidal against many Gram-positive and -negative microorganisms, is commonly prescribed for the treatment of a variety of infections. Successful therapy with ciprofloxacin requires the achievement of adequate drug concentrations in the serum or urine. However, the formation of chelate complexes between ciprofloxacin and cations in phosphate binding agents may result in a reduction in systemic availability of the former, which may in turn compromise the antimicrobial therapy. The oral bioavailability of ciprofloxacin is reported to be approximately 70% (14). Previous studies have shown a significant reduction in the oral bioavailability and Cmax of ciprofloxacin when administered with calcium carbonate, calcium acetate, or sevelamer. Frost et al. (3) and Sahai et al. (4) investigated the effects of calcium carbonate on the absorption of ciprofloxacin. Their results showed that the relative oral bioavailability of ciprofloxacin was reduced by 40 and 43% (P < 0.05), and Cmax was reduced by 47 and 40% (P < 0.05), respectively. In another study, concomitant administration of ciprofloxacin with calcium acetate decreased the relative oral bioavailability and Cmax of ciprofloxacin by 51 and 52%, respectively (P < 0.05) (6). It was also determined that there was a 48% reduction in ciprofloxacin oral bioavailability (P < 0.05) and 27% reduction in Cmax (P < 0.05) when it was administered with sevelamer, a calcium- and aluminum-free, nonabsorbable cationic polymer phosphate binding agent (6).

Administration of lanthanum carbonate has not been shown to affect the pharmacokinetics of digoxin, metoprolol, or warfarin (15–18). In addition, a physicochemical interaction (precipitation) was not observed in simulated gastric fluid between lanthanum carbonate and warfarin, digoxin, furosemide, phenytoin, metoprolol, or enalapril. This suggests that the formation of insoluble complexes in the gastrointestinal tract between these drugs and lanthanum is unlikely (19). However, no study has investigated the potential effects of lanthanum carbonate on the absorption of fluoroquinolone antibiotics, specifically ciprofloxacin.

Results from this study showed slightly greater reductions in the systemic availability (54%; P < 0.001) and Cmax (56%; P < 0.001) of ciprofloxacin when administered with lanthanum carbonate compared with studies using other phosphate binders. On the basis of the accompanying change in urinary ciprofloxacin recovery and the close correlation between the change in fraction of ciprofloxacin recovered and change in AUC, coupled with the lack of significant change in Tmax, t1/2, and Clrenal of ciprofloxacin with and without lanthanum carbonate, it can be concluded that the reduction in ciprofloxacin AUC was related to the decrease in its extent of absorption when administered with lanthanum carbonate.

Although the mean reduction in ciprofloxacin systemic availability was 54% when administered with lanthanum carbonate, the change in ciprofloxacin pharmacokinetics among our study participants varied greatly. Of note, nine of the 12 participants exhibited a ≥30% (range 30 to 73%) reduction in systemic ciprofloxacin availability when co-administered with lanthanum carbonate. In contrast, the reduction in systemic availability in the other three participants was only 6 to 24%. Despite such interindividual variability in the results, the reduction in urinary ciprofloxacin recovery corresponds very well with the decrease in AUC in all of the participants. This suggests that the interaction between ciprofloxacin and lanthanum carbonate is caused by the reduction of ciprofloxacin absorption by lanthanum.

The effectiveness of antimicrobial agents critically depends on the concentrations attained in body fluids. The minimum inhibitory concentration of ciprofloxacin against most susceptible organisms falls in the range of 0.5 to 4 mg/L (20). Because the Cmax that is attained after a 750-mg dose of ciprofloxacin ranges from 2.6 to 3.4 µg/ml (21–24), a 56% reduction in ciprofloxacin Cmax by lanthanum would put patients at risk for prolonged periods of subtherapeutic concentration within the dosing interval. The therapeutic efficacy of ciprofloxacin may thus be compromised.

On the basis of the results of this study, it is prudent to avoid concomitant administration of oral ciprofloxacin and lanthanum carbonate in patients with CKD; however, the optimal length of time necessary to separate the administration of these two drugs is not known. Avoiding administration of ciprofloxacin 2 h before or 2 h after the ingestion of calcium carbonate did not result in significant change in the relative bioavailability of the antibiotic (25,26). However, according to the prescribing information for Cipro (ciprofloxacin hydrochloride) (27), it is recommended that ciprofloxacin be taken 2 h before or 6 h after calcium-containing products, whereas that of Renagel (sevelamer hydrochloride) (28) recommends taking ciprofloxacin at least 1 h before or 3 h after sevelamer. Results from this study showed that the time needed to reach ciprofloxacin Cmax was between 0.75 and 2 h when ciprofloxacin was given alone and between 1 and 4 h when administered with lanthanum carbonate. To avoid the pharmacokinetic interaction between the two drugs, ciprofloxacin should be taken at least 2 h before or 4 h after lanthanum carbonate. Patients with CKD usually take lanthanum carbonate three times daily with meals. To facilitate the administration of lanthanum carbonate and ciprofloxacin and to avoid any drug interaction, bedtime dosing of ciprofloxacin in these patients seems to be optimal.


   Conclusions
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
 Conclusions
Disclosures
 References
 
This study showed a significant reduction in the systemic availability of ciprofloxacin when administered with lanthanum carbonate. The reduction in absorption is significant in most individuals. Concomitant administration of both drugs should therefore be avoided to prevent suboptimal response to ciprofloxacin.


   Disclosures
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
 Conclusions
 Disclosures
References
 
None.


   Acknowledgments
 
This project was supported by a grant from the Shire US Inc. investigator-initiated trial program.

We thank Patricia Fischer, RN, for assistance in this study.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received April 5, 2007. Accepted June 20, 2007.


   References
Top
 Abstract
 Introduction
 Concise Methods
 Results
 Discussion
 Conclusions
 Disclosures
 References
 

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  27. Product information: Cipro® (ciprofloxacin hydrochloride), West Haven, CT, Bayer Pharmaceuticals Corp.,2005
  28. Product information: Renagel® (sevelamer hydrochloride), Cambridge, MA, Genzyme Corp.,2004




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