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

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,

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