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

Priscilla P. How,* James H. Fischer,* Jose A. Arruda,† and Alan H. Lau* Departments of *Pharmacy Practice and †Medicine (Section of Nephrology), University of Illinois at Chicago, Chicago, Illinois

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. Clin J Am Soc Nephrol 2: 1235–1240, 2007. doi: 10.2215/CJN.01580407

yperphosphatemia is common in patients with decrease the absorption and oral bioavailability of ciprofloxacin chronic kidney disease (CKD) because of their im- (4,6). H paired renal phosphorus excretion, resulting in sec- Lanthanum carbonate is a recently available phosphate bind- ondary hyperparathyroidism and renal osteodystrophy. Pa- ing agent that is effective for the management of hyperphos- tients who have stage 5 CKD and undergo hemodialysis are phatemia and in preventing secondary hyperparathyroidism also more susceptible to bacterial infections and are therefore at (7–10). Lanthanum is a naturally occurring rare earth element risk for increased morbidity and mortality (1). Broad-spectrum that shares some similar chemical properties as aluminum. fluoroquinolone antimicrobial agents, such as ciprofloxacin, Upon administration of lanthanum carbonate, lanthanum ions may be used in these patients because they are commonly are released in the upper gastrointestinal tract and reduce the absorption of dietary phosphorus and may also bind to other prescribed for the treatment of infections caused by Gram- drugs that are concomitantly administered, thereby reducing positive and -negative microorganisms, including Pseudomonas their bioavailability. However, there is limited information re- aeruginosa. garding such drug interactions with lanthanum carbonate. This The absorption and oral bioavailability of ciprofloxacin are study was therefore conducted to determine whether a signif- affected by calcium-, magnesium-, and aluminum-containing icant pharmacokinetic interaction exists between lanthanum salts (2–4). When administered concomitantly, chelate com- carbonate and ciprofloxacin. plexes are formed between the metal cations and ciprofloxacin, resulting in reduced bioavailability of the quinolone (5). Phos- phate binders such as calcium carbonate, calcium acetate, and Concise Methods sevelamer, a cationic polymer, have also been demonstrated to 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 Received April 5, 2007. Accepted June 20, 2007. child-bearing potential were eligible for participation provided that Published online ahead of print. Publication date available at www.cjasn.org. they had a negative urine pregnancy test and were using an effective means of contraception or abstaining from sexual activity. Individuals Correspondence: Dr. Alan H. Lau, Department of Pharmacy Practice, College of were excluded from study participation when they had a known al- 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: lergy to fluoroquinolone antibiotics, history of dysphagia, or swallow- [email protected] ing disorders or gastrointestinal condition that may interfere with

Copyright © 2007 by the American Society of Nephrology ISSN: 1555-9041/206–1235 1236 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1235–1240, 2007 absorption of the study drugs or were taking medications that might (Pharsight Corp., Mountain View, CA). Maximum plasma concen- interact with ciprofloxacin or lanthanum carbonate. The study was tration (Cmax) and time of maximum plasma concentration (Tmax) approved by the institutional review board at the University of Illinois were obtained directly from the observed ciprofloxacin plasma con- at Chicago. Participants provided written informed consent before the centration curves. When two maximal values were observed, the initiation of any study procedures. first was designated as Tmax. The terminal elimination rate constant (k) was estimated by log-linear regression of the terminal exponen- Study Design tial portion of the plasma concentration–time curves based on at

This was an open-label, two-way, crossover study. The order of each least three time points. The elimination half-life (t1⁄2) was determined treatment arm was randomly assigned, with a washout interval of 7 to by dividing 0.693 by k. The area under the plasma concentration

14 d between arms. All participants abstained from alcohol and caf- time curve from time 0 to infinity (AUC0toϱ) was calculated from feine-containing food or beverages during the study. They were also time 0 to the last measurable serum concentration (AUC0tot)bythe instructed not to take any new medications from 1 wk before the study trapezoid rule (linear trapezoidal up to Cmax and log trapezoidal until after study completion. from Cmax to the last measurable plasma concentration), with ex- In study arm A, participants received a single oral dose of ciprofloxa- trapolation to infinity by dividing the last observed concentration cin 750 mg (Cipro; Bayer Corp., West Haven, CT). In arm B, lanthanum by k. carbonate was administered with ciprofloxacin. For simulation of the The amount of unchanged ciprofloxacin excreted in the urine clinical use of the drug, lanthanum carbonate 1000-mg chewable tablet during 24 h (mg) was determined from the sum of the products of (Fosrenol; Shire US Inc., Wayne, PA) was administered orally three urine volume and ciprofloxacin concentration for each collection times a day with meals for 2 consecutive days. On the second day of interval during the 24 h after ciprofloxacin administration. The lanthanum carbonate administration, a single dose of ciprofloxacin 750 fraction of the dose excreted as ciprofloxacin in the urine was mg was administered immediately after the morning dose of lantha- calculated by dividing the amount of unchanged ciprofloxacin ex- num carbonate. Participants received a standardized breakfast that creted in the urine during 24 h by 750 mg. Renal clearance (Clrenal) consisted of two slices of bread with butter and grape jam on all study of ciprofloxacin was calculated by dividing the amount of cipro- visit days. Participants fasted for at least 8 h before ciprofloxacin floxacin excreted in the urine during 24 h by the ciprofloxacin AUC administration, but no restrictions were placed on the amount of drink- from time 0 to 24 h. ing water. The same lots of ciprofloxacin and lanthanum carbonate doses were used throughout the study. The participants were also Statistical Analyses asked to fill out a questionnaire to report any adverse effects at the end Assuming an interindividual coefficient variation of 15 to 25% for of each study visit. AUC0toϱ, a sample size of 11 to 15 was estimated to provide at least 80% power to detect a 25% difference in AUC0toϱ between study arms using Blood and Urine Sampling a two-sided test and ␣ of 0.05. The pharmacokinetic values for each An indwelling peripheral venous catheter was placed for serial blood treatment are expressed as the geometric mean and coefficient of vari- sampling and was kept patent with normal saline flush. Blood samples, ation, with the exception of Tmax, which is expressed as the median and approximately 6 ml each, were collected from the participants at the range. An ANOVA for repeated measures was performed to assess following times: Immediately before ciprofloxacin administration and differences with and without lanthanum co-administration for cipro-

0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after ciprofloxacin 1 floxacin Cmax, AUC0toϱ,t⁄2, Clrenal, and fraction of the dose excreted in ingestion. The blood samples were collected in Vacutainer tubes that the urine as ciprofloxacin. The parameters were logarithmically (natu- contained heparin (BD Vacutainer, Becton, Dickinson and Company, ral) transformed for the ANOVA. The ANOVA model included se- Franklin Lakes, NJ). After collection, the blood samples were centri- quence, period, and treatment as fixed effects and subject within se- ϫ fuged at 1000 g for 10 min within1hofcollection. The plasma was quence as a random effect. The 90% confidence intervals (CI) were Ϫ then separated, transferred into cryovials, and stored at 20°C until calculated for the difference between the ciprofloxacin plus lanthanum assayed. and ciprofloxacin alone treatment means. The anti-logs of the differ- The participants emptied their bladder before the start of the study, ences between treatment means and upper and lower confidence limits and urine was collected at the following time intervals: 0 to 2, 2 to 4, 4 were then obtained to provide for each parameter the ratio of the to 6, 6 to 8, 8 to 12, and 12 to 24 h after ciprofloxacin administration. The geometric means and 90% CI for the ratio. The lack of a clinically total urine volume was recorded, and a 5-ml aliquot from each collec- significant interaction was concluded when the 90% CI for the ratios Ϫ tion period was stored at 20°C until analysis. were within the equivalence limits of 80 to 125%, as recommended by the US Food and Drug Administration guidelines on bioequivalence

Sample Analysis (13). The difference in Tmax values between treatments was compared Plasma concentrations of ciprofloxacin were quantified by HPLC using the Wilcoxon signed rank test. Nonparametric 90% CI were according to the method reported by Granneman and Varga (12). The constructed around the median difference in Tmax between treatments. assay was linear from the range of 0.0088 to 5.45 ␮g/ml of ciprofloxacin Pharmacokinetic and statistical analyses were performed using Win- in plasma and from the range of 0.104 to 20.8 ␮g/ml of ciprofloxacin in Nonlin version 4.1. urine. The minimum quantifiable concentration of ciprofloxacin was 0.0088 ␮g/ml in plasma and 0.104 ␮g/ml in urine. The interday coef- ficient of variation for replicate samples (n ϭ 7) varied from 1.6 to 2.2% Results within the concentration range of the plasma standard curve and from A total of 14 healthy individuals consented to participate in the 1.1 to 1.4% within the concentration range of the urine standard curve. study. Two withdrew consent because of nausea and vomiting (one participant) and difficulty in placing the peripheral venous Pharmacokinetic Analysis catheter (one participant); therefore, 12 participants (six men, Plasma concentration versus time data for ciprofloxacin were an- six women; aged 26 to 50 yr) completed the study. Of these, alyzed by noncompartmental methods using WinNonlin version 4.1 seven were white, four were Asian, and one was Hispanic. Clin J Am Soc Nephrol 2: 1235–1240, 2007 Lanthanum and Ciprofloxacin Drug Interaction 1237

Their mean (range) weight and height were 72.1 kg (53 to 93 kg) encing at least one adverse effect. Nausea was most commonly and 172.8 cm (155 to 193 cm), respectively. None of the partic- experienced, followed by abdominal pain, bloating, headache, ipants was a smoker. Medications taken by the participants and dizziness. None of the adverse effects was severe enough included inhaled albuterol, montelukast, desloratadine, glu- in nature to require discontinuation from the study. cosamine, atorvastatin, and oral contraceptives, none of which has documented drug interaction with the study medications. Discussion The concurrent drugs and dosages remained the same through- Ciprofloxacin, a broad-spectrum fluoroquinolone antibiotic out the study period. that is bactericidal against many Gram-positive and -negative Figure 1 shows the mean Ϯ SE ciprofloxacin plasma concen- microorganisms, is commonly prescribed for the treatment of a tration–time curves with and without concurrent lanthanum variety of infections. Successful therapy with ciprofloxacin re- treatment. The parameters describing the pharmacokinetics of quires the achievement of adequate drug concentrations in the ciprofloxacin in each study arm are presented in Table 1. Co- serum or urine. However, the formation of chelate complexes administration of lanthanum significantly (P Ͻ 0.001) de- between ciprofloxacin and cations in phosphate binding agents creased the ciprofloxacin Cmax by 56% and the AUC0toϱ by may result in a reduction in systemic availability of the former, 54%. Correspondingly, the fraction of the dose recovered as which may in turn compromise the antimicrobial therapy. The ciprofloxacin in the urine during 24 h declined by 52% with oral bioavailability of ciprofloxacin is reported to be approxi- lanthanum administration. The 90% CI of the geometric mean mately 70% (14). Previous studies have shown a significant ϩ ratios [(ciprofloxacin lanthanum)/ciprofloxacin alone] for reduction in the oral bioavailability and Cmax of ciprofloxacin

Cmax, AUC0toϱ, and fraction recovered in urine as ciprofloxa- when administered with calcium carbonate, calcium acetate, or cin fell below the lower equivalent limits of 0.80 (13). The Tmax, sevelamer. Frost et al. (3) and Sahai et al. (4) investigated the

1 Ͼ t ⁄2, and Clrenal for ciprofloxacin were similar (P 0.05) in the effects of calcium carbonate on the absorption of ciprofloxacin. absence or presence of lanthanum, with the 90% CI for the Their results showed that the relative oral bioavailability of

1 Ͻ geometric mean ratios of t ⁄2 and Clrenal falling within the no ciprofloxacin was reduced by 40 and 43% (P 0.05), and Cmax interaction limits of 0.8 to 1.25. was reduced by 47 and 40% (P Ͻ 0.05), respectively. In another

Figure 2 shows the individual changes in AUC0toϱ between study, concomitant administration of ciprofloxacin with cal- treatment arms. The AUC0toϱ decreased in all participants cium acetate decreased the relative oral bioavailability and Ͻ when lanthanum was co-administered. The decline among in- Cmax of ciprofloxacin by 51 and 52%, respectively (P 0.05) (6). dividuals ranged from 6 to 73%. Figure 3 shows the fraction of It was also determined that there was a 48% reduction in ciprofloxacin dose recovered in the urine during 24 h for the ciprofloxacin oral bioavailability (P Ͻ 0.05) and 27% reduction Ͻ individual participants. in Cmax (P 0.05) when it was administered with sevelamer, a Both study medications were generally well tolerated. Two calcium- and aluminum-free, nonabsorbable cationic polymer participants experienced headache when ciprofloxacin was ad- phosphate binding agent (6). ministered alone; the remaining participants did not report any Administration of lanthanum carbonate has not been shown adverse events. When ciprofloxacin was co-administered with to affect the pharmacokinetics of digoxin, metoprolol, or war- lanthanum carbonate, all participants but one reported experi- farin (15–18). In addition, a physicochemical interaction (pre-

Figure 1. Plasma concentration (mean Ϯ SE) versus time curves for ciprofloxacin when administered alone and with lanthanum carbonate. 1238 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1235–1240, 2007

Table 1. Summary of ciprofloxacin pharmacokinetic parameters after administration of ciprofloxacin alone and ciprofloxacin with lanthanum carbonatea ϩ b Ciprofloxacin Ratio of Geometric Means P Parameter Ciprofloxacin Alone Lanthanum (90% CI) ␮ Ͻ AUC0toϱ ( g-h/ml) 17.7 (28.6) 8.2 (31.8) 0.46 (0.38 to 0.57) 0.001 ␮ Ͻ Cmax ( g/ml) 3.3 (31.1) 1.4 (60.3) 0.44 (0.31 to 0.62) 0.001 c Ϫ Ϫ c Tmax (h, median [range]) 1.5 (0.75 to 2.03) 1.24 (0.50 to 4.05) 0.12 ( 0.76 to 0.51) 0.75 t1/2 (h) 4.9 (16.4) 5.4 (13.4) 1.09 (0.99 to 1.19) 0.12 Clrenal (ml/min) 226 (26.4) 235 (23.6) 1.04 (0.97 to 1.12) 0.35 Fraction of dose excreted into 0.31 (20.2) 0.15 (35.8) 0.48 (0.39 to 0.58) Ͻ0.001 urine as ciprofloxacin during 24 h

a AUC0toϱ, area under the plasma concentration–time curve from time 0 to infinity; CI, confidence interval; Clrenal, renal clearance; Cmax, maximum plasma concentration; Tmax, time of maximum plasma concentration; t1/2, elimination half-life. b Parameters are expressed as geometric mean (% coefficient of variation), except for Tmax. cMedian difference and 90% CI of difference.

Figure 2. Comparison of the area under plasma concentration–time curves from time 0 to infinity (AUC0toϱ) between the two arms for individual participants (dotted lines). The solid line represents the mean AUC0toϱ for all participants.

cipitation) was not observed in simulated gastric fluid between cin recovery and the close correlation between the change in lanthanum carbonate and warfarin, digoxin, furosemide, phe- fraction of ciprofloxacin recovered and change in AUC, cou-

1 nytoin, metoprolol, or enalapril. This suggests that the forma- pled with the lack of significant change in Tmax,t⁄2, and Clrenal tion of insoluble complexes in the gastrointestinal tract between of ciprofloxacin with and without lanthanum carbonate, it can these drugs and lanthanum is unlikely (19). However, no study be concluded that the reduction in ciprofloxacin AUC was has investigated the potential effects of lanthanum carbonate related to the decrease in its extent of absorption when admin- on the absorption of fluoroquinolone antibiotics, specifically istered with lanthanum carbonate. ciprofloxacin. Although the mean reduction in ciprofloxacin systemic avail- Results from this study showed slightly greater reductions in ability was 54% when administered with lanthanum carbonate, Ͻ Ͻ the systemic availability (54%; P 0.001) and Cmax (56%; P the change in ciprofloxacin pharmacokinetics among our study 0.001) of ciprofloxacin when administered with lanthanum car- participants varied greatly. Of note, nine of the 12 participants bonate compared with studies using other phosphate binders. exhibited a Ն30% (range 30 to 73%) reduction in systemic On the basis of the accompanying change in urinary ciprofloxa- ciprofloxacin availability when co-administered with lantha- Clin J Am Soc Nephrol 2: 1235–1240, 2007 Lanthanum and Ciprofloxacin Drug Interaction 1239

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.

num carbonate. In contrast, the reduction in systemic availabil- (28) recommends taking ciprofloxacin at least 1 h before or ity in the other three participants was only 6 to 24%. Despite 3 h after sevelamer. Results from this study showed that the such interindividual variability in the results, the reduction in time needed to reach ciprofloxacin Cmax was between 0.75 urinary ciprofloxacin recovery corresponds very well with the and 2 h when ciprofloxacin was given alone and between 1 decrease in AUC in all of the participants. This suggests that the and 4 h when administered with lanthanum carbonate. To interaction between ciprofloxacin and lanthanum carbonate is avoid the pharmacokinetic interaction between the two caused by the reduction of ciprofloxacin absorption by lantha- drugs, ciprofloxacin should be taken at least 2 h before or 4 h num. after lanthanum carbonate. Patients with CKD usually take The effectiveness of antimicrobial agents critically depends lanthanum carbonate three times daily with meals. To facil- on the concentrations attained in body fluids. The minimum itate the administration of lanthanum carbonate and cipro- inhibitory concentration of ciprofloxacin against most suscep- floxacin and to avoid any drug interaction, bedtime dosing tible organisms falls in the range of 0.5 to 4 mg/L (20). Because of ciprofloxacin in these patients seems to be optimal. the Cmax that is attained after a 750-mg dose of ciprofloxacin ranges from 2.6 to 3.4 ␮g/ml (21–24), a 56% reduction in ciprofloxacin Cmax by lanthanum would put patients at risk for Conclusions prolonged periods of subtherapeutic concentration within the This study showed a significant reduction in the systemic avail- dosing interval. The therapeutic efficacy of ciprofloxacin may ability of ciprofloxacin when administered with lanthanum thus be compromised. carbonate. The reduction in absorption is significant in most On the basis of the results of this study, it is prudent to individuals. Concomitant administration of both drugs should avoid concomitant administration of oral ciprofloxacin and therefore be avoided to prevent suboptimal response to cipro- lanthanum carbonate in patients with CKD; however, the floxacin. optimal length of time necessary to separate the administra- tion of these two drugs is not known. Avoiding administra- Acknowledgments tion of ciprofloxacin 2 h before or 2 h after the ingestion of This project was supported by a grant from the Shire US Inc. inves- calcium carbonate did not result in significant change in the tigator-initiated trial program. relative bioavailability of the antibiotic (25,26). However, We thank Patricia Fischer, RN, for assistance in this study. according to the prescribing information for Cipro (cipro- floxacin hydrochloride) (27), it is recommended that cipro- floxacin be taken 2 h before or 6 h after calcium-containing Disclosures products, whereas that of Renagel (sevelamer hydrochloride) None. 1240 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 2: 1235–1240, 2007

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