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Clinical Therapeutics/Volume 34, Number 6, 2012

Assessment of Pharmacodynamic Equivalence andTolerability of Lanthanum Carbonate Oral Powderand Tablet Formulations: A Single-Center, Randomized,Open-Label, 2-Period Crossover Study in Healthy Subjects

David Pierce, PhD1; Stuart Hossack, BSc2; Antoine Robinson, MSN, CRNP3;inggao Zhang, PhD3; and Patrick Martin, MD3

1Shire Pharmaceutical Development Ltd, Basingstoke, United Kingdom; 2Covance Clinical Research UnitLtd, Leeds, United Kingdom; and 3Shire Pharmaceuticals Inc, Wayne, Pennsylvania

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ABSTRACTBackground: Phosphate binders are commonly used

n tablet form to help patients with hyperphos-hatemia limit their absorption of dietary phosphate.hese patients frequently have a heavy tablet burden solternative formulations provide choice and may sup-ort adherence. Lanthanum carbonate (LC) is a phos-hate binder currently available as a chewable tablet.his study was conducted to support an application forarketing authorization for the oral powder formula-

ion within the European Union.Objective: The goal of this study was to examine the

harmacodynamics, pharmacokinetics, and tolerabil-ty of an oral powder formulation of LC comparedith the reference chewable tablet formulation.Methods: A Phase I, single-center, randomized,

pen-label, 2-period, crossover study to assess phar-acodynamic equivalence of the 2 formulations was

onducted in healthy adults aged 18 to 55 years receiv-ng a diet standardized for phosphate content. Individ-als were randomized to receive a different formula-ion in each period, taking 10 doses of 1000-mg LC at000 mg/d per period with an intervening washout of14 days. The primary pharmacodynamic variableas mean daily excretion of urinary phosphorus overdays while receiving LC. Pharmacodynamic equiva-

ence was confirmed if the 90% CI for the differenceetween formulations in least squares (LS) mean ex-reted urinary phosphorus was within �20% of the LS

mean value for the tablet formulation. Secondary endpoints included determination of pharmacokinetic pa-rameters and assessment of tolerability by recording ofadverse events.

Results: In total, 72 individuals entered the study.

They were predominantly men (72.2%), with a mean

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(SD) age of 31.4 (8.26) years and a BMI of 25.8 (2.45)kg/m2. The LS mean (SE) excreted urinary phosphoruswas 16.8 (0.48) mmol/d during administration of LCtablets (�20% � �3.35 mmol/d). The correspondingvalue during administration of LC oral powder was15.2 (0.48) mmol/d; 90% CI for the difference betweenformulations was �2.38 to �0.82 mmol/d, confirmingpharmacodynamic equivalence. The most commonadverse events were gastrointestinal, and no seriousadverse events were recorded.

Conclusions: In this multiple-dose study, the oralpowder and tablet formulations of LC were well tol-erated and met the regulatory criteria for pharmaco-dynamic equivalence in these healthy volunteers.ClinicalTrials.gov identifier: NCT00880750. (ClinTher. 2012;34:1290–1300) © 2012 Elsevier HSJournals, Inc. All rights reserved.

Key words: chronic kidney disease, hyperphos-hatemia, lanthanum carbonate, oral powder, phos-hate binder.

INTRODUCTIONRenal function progressively declines in patients withchronic kidney disease (CKD) and, as a consequence,the body’s ability to excrete phosphate decreases. Ho-meostatic mechanisms keep serum phosphorus levelswithin the normal physiologic range until patientsreach the later stages of CKD (stages 4 and 5)1; theormal physiologic range for serum phosphorus is 0.8o 1.5 mmol/L (2.5–4.5 mg/dL). However, up to 80%

Accepted for publication May 10, 2012.http://dx.doi.org/10.1016/j.clinthera.2012.05.0030149-2918/$ - see front matter

© 2012 Elsevier HS Journals, Inc. All rights reserved.

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of patients with CKD stage 5 develop hyperphos-phatemia and, despite receiving maintenance dialysis,their serum phosphorus concentration can exceed 2.1mmol/L (6.5 mg/dL).2 Serum phosphorus concentra-ions at this level are associated with a significantlyigher risk of morbidity and mortality,3,4 and the Kid-ey Disease: Improving Global Outcomes guidelinesecommend that serum phosphorus levels in dialysisatients with CKD stage 5 should be lowered as closeo the normal range as possible and should be main-ained within the normal range in patients with earliertage CKD.5 Patients with CKD commonly take phos-

phate binders at meal times and observe dietary restric-tions to control their serum phosphorus levels. Adher-ence to a low-phosphate diet may help to achieve targetphosphorus levels, but such diets are commonly asso-ciated with a reduction in protein intake.6,7 The in-crease in mortality risk posed by restricting proteinmay nonetheless outweigh the benefits of controllingserum phosphorus levels.7 Patients therefore combinephosphate-binder treatment with a protein- and phos-phate-controlled diet.

Calcium-based phosphate binders are widely usedbut have limitations in that their capacity per tablet tobind dietary phosphate is lower than that of some otherforms of phosphate binder.8,9 Furthermore, recom-mendations have been made to restrict the use of cal-cium-based binders in patients with hypercalcemia,arterial calcification, adynamic bone disease, or hypo-parathyroidism.5 Sevelamer carbonate has a relativelymodest capacity to bind phosphate,8,9 and has beeneported to reduce the oral bioavailability of vitamin Dupplements, which are commonly taken by patientsith CKD.8,10 Lanthanum carbonate* is a phosphate

binder with high binding potential that is currentlyavailable as a chewable tablet. Stomach acid releaseslanthanum ions, which form highly insoluble lantha-num phosphate complexes that are subsequently ex-creted in feces. Studies in healthy volunteers,11 patientsnot yet undergoing dialysis,12 and those receiving long-term renal replacement therapy13 have reported theeffectiveness of this binder. Recently, lanthanum car-bonate has been reformulated as an oral powder thatmay be taken mixed with soft food. This new formu-lation offers patients both choice and flexibility of ad-ministration, which may support improved adherence.

*Trademark: FOSRENOL® (Shire Pharmaceuticals, Nyon,

Switzerland).

June 2012

A Phase I, single-center, randomized, open-label,2-period, crossover study was conducted in healthyindividuals with the objective of comparing the phar-macodynamics, pharmacokinetics, and tolerability ofthe oral powder formulation with those of the chew-able tablet. Urinary phosphate excretion was used as asurrogate for intestinal phosphate absorption becausehomeostatic mechanisms maintain a neutral phosphatebalance in healthy individuals and any excess phos-phate is excreted through the kidneys.14 This study wasonducted to support an application for marketing au-horization for the oral powder formulation within theuropean Union.

SUBJECTS AND METHODSSubjects

Healthy men and women aged 18 to 55 years with abody mass index in the range of 20.0 to 29.9 kg/m2

were enrolled in the study. Exclusion criteria included:a current or recurrent disease that could affect the ac-tion, absorption, or disposition of the test (oral pow-der) and reference (chewable tablets) product or clini-cal or laboratory values; clinically significant abnormalserum phosphorus levels outside the normal range(0.96–1.45 mmol/L [3.0–4.5 mg/dL]); known or sus-pected intolerance or hypersensitivity to lanthanumcarbonate; allergy to milk or other foods included in astandardized phosphate diet; inability to follow the di-etary requirements of the study; being actively enrolledin a drug or vaccine trial or use of another investiga-tional product up to 30 days before the first study dose;use of any medication (including over-the-counter,multivitamin, herbal, or homeopathic preparations)with the exception of hormonal replacement therapyor hormonal contraceptives within 7 days of the firststudy dose; men consuming �3 units of alcohol perday; women consuming �2 units of alcohol per day; apositive screen for alcohol or drug abuse; and use oftobacco or other nicotine-containing products in anyform.

All individuals provided written informed consentbefore screening. The study was conducted in accor-dance with the International Conference on Harmoni-sation Good Clinical Practice Guideline E615 and wasapproved by Aspire IRB (Santee, California).

Study DesignThis was a Phase I, randomized, open-label, 2-pe-

riod, crossover study conducted at a single clinical re-

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search center (CRC; West Coast Clinical Trials, Cy-press, California) between January 28 and June 22,2009. The study design was based on previously pub-lished methods for evaluation of phosphorus absorp-tion in healthy subjects, and the 4-day, multiple-doseregimen enabled determination of average phosphateexcretion over 3 days to allow for between-dayvariability.11,16

For each individual, screening and confirmation ofeligibility and informed consent was conducted duringthe 28 days before the first dose being given. Eachindividual was allocated a unique randomization num-ber once their eligibility had been confirmed. Therewere 2 dosing periods separated by a washout period.Individuals were randomized to treatment sequenceimmediately after breakfast on day 1 of the first dosingperiod to receive either oral powder or chewable tab-lets; in the second dosing period, they received the al-ternative formulation. A sufficient number of individ-uals were randomized to ensure that �46 individualscompleted the study. In each dosing period, individualswere confined to the CRC for 9 days (ie, days �3 to 6)and received a standardized phosphate-controlled dietfor 6 days (ie, days �2 to 4). This diet contained anapproximate total phosphate content of 1300 mg/d,with a total calorific content of 2500 kcal/d, and wasdivided approximately equally between the 3 dailymeals. Individuals received normal meals provided bythe CRC on day �3 and following completion of theevening meal on day 4 of each dosing period. Individ-uals received a 1000-mg dose of lanthanum carbonateTID immediately after meals on days 1 to 3 and afterthe morning meal on day 4, for a total of 10 doses. Oralpowder (1000-mg sachet; batch 807012; expiry, July17, 2010) was sprinkled on a tablespoon of apple sauceimmediately before consumption, and the tablet (1000mg; batch A38683B; expiry, July 31, 2010) waschewed before swallowing, followed immediately byingestion of a tablespoon of apple sauce. After eachdose of the oral powder or chewable tablet, all individ-uals drank 240 mL of distilled water. Individuals weredischarged from the CRC for at least 8 days betweendosing periods to provide a washout period of �14days; the total study duration was 28 days.

Pharmacodynamic AssessmentIn each dosing period, urine was collected over

5 days (days �2 to 4) and pooled for analysis every

4 hours. Collection of each 24-hour pooled sample t

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began and finished 30 minutes before the morningmeal on consecutive days (ie, the pooled sample desig-nated day �1 was collected between the morning ofday �2 and the morning of day �1; the day 1 samplewas collected between day �1 and day 1; the finalpooled sample [ie, the day 4 sample] was collected be-tween day 3 and day 4). The primary pharmacody-namic variable was average daily urinary phosphateexcretion during the 3 days of lanthanum carbonatetreatment (the 3 collection periods ending on days 2, 3,and 4). The secondary pharmacodynamic variable wasurinary phosphate excretion in the pooled samplescompleted on day 4 only. Baseline values were the av-erage phosphate content of the pooled samples com-pleted on days �1 and 1. Urinary phosphate concen-trations were determined at Huntingdon Life Sciences(Huntingdon, United Kingdom) by using a previouslyvalidated Roche P Modular analyzer method (Hitachi917A, Roche Diagnostics, Lewis, United Kingdom).The lower limit of quantitation was 3 mmol/L, and theupper limit of quantitation was 50 mmol/L for phos-phate in urine. The interday precision (expressed as%CV) values ranged from 1.8% to 2.3%. Accuracy(expressed as %bias) ranged from 1.4% to 10.7%. Inaddition, �9% of the study samples were subjected toincurred sample reanalysis. At least 93% (54 of 58) ofthe re-assayed results agreed within �20% of the meanof the original and the reassayed results.

Pharmacokinetic AssessmentPredose blood samples were drawn 30 minutes be-

fore the morning meal on days 1 to 4 and at varioustimes (3, 4, 5, 6, 8, 12, 18, 24, 36, and 48 hours) afterthe last dose on day 4, representing �4 t½ from thetime of the first dose.17 Blood samples were chilled onrushed ice immediately after collection, and thelasma fraction was isolated by centrifugation within0 minutes. Plasma lanthanum concentrations wereetermined at Research Triangle Institute (Researchriangle Park, North Carolina) using a previously val-

dated inductively coupled plasma mass spectrometryethod conducted on a Thermo X7 ICP-MS (Thermoisher Scientific, Waltham, Massachusetts). The lower

imit of quantitation was 0.0312 ng/mL, and the upperimit of quantitation was 2.0000 ng/mL for lanthanumn plasma. The interday %CV values for the qualityontrol samples ranged from 2.7% to 4.3%, and thebias values ranged from �2.2% to 0.9%. In addi-

ion, �7% of the study samples (121 of 1726) were

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subjected to incurred sample reanalysis. At least 86%(104 of 121) of the reassayed results agreed within�20% of the mean of the original and the reassayedresults.

Pharmacokinetic parameters, determined usingnoncompartmental techniques18 via WinNonlin ver-sion 5.2 (Pharsight Corporation, Mountain View, Cal-ifornia), included Cmax, Tmax, AUC0–48 (calculated us-ing the linear trapezoidal method when concentrationsincreased and the logarithmic trapezoidal rule whenconcentrations decreased), and t½. These parameters

ere selected for consistency with a standard protocolsed previously for comparing different lanthanumarbonate formulations.

TolerabilityTolerability was assessed by collation of adverse

events (AEs) at regular intervals throughout the study.AE questioning and reporting was conducted dailyduring confinement (days �3 to 6 of each treatmentperiod) and at follow-up (7 days after the final dose ofstudy medication) and participants were encouraged tospontaneously report AEs as they became aware ofthem. Data for AEs were analyzed using the treatment-emergent signs and symptoms philosophy and werecoded using the Medical Dictionary for RegulatoryActivities version 12.0. Treatment-emergent AEs(TEAEs) were defined as AEs that emerged duringtreatment having been absent at baseline; re-emergedduring treatment having been present at baseline buthaving stopped before treatment; or worsened in sever-ity during treatment relative to baseline when the AEwas continuous. Frequency of TEAEs was calculatedby preferred term and by treatment for the number ofindividuals and percentage reporting the event. Theseverity of the AEs and the relationship to formulationwere summarized.

Statistical AnalysisAll safety and pharmacodynamic analyses were per-

formed by Data Virtuoso, Inc (Collegeville, Pennsylva-nia). Statistical programming and analyses were per-formed using SAS version 9.2 (SAS Institute, Inc, Cary,North Carolina). Individuals included in the safety settook at least 1 dose of lanthanum carbonate and had atleast 1 postdose tolerability assessment. The pharma-codynamic set included all evaluable individuals in thesafety set who completed all urine collections and con-

sumed at least 95% of food in all treatment periods. w

June 2012

Individuals who vomited between days �2 and 4 in adosing period were excluded because the retaineddoses and quantities of dietary phosphate available forabsorption in these individuals would not be knownwith any degree of confidence. At least 23 individualsper treatment sequence were required to complete thestudy. The sample size estimation was based on reduc-tions in urinary phosphate excretion seen in previousShire-sponsored studies,11 assuming that average uri-ary phosphate excretion after treatment with chew-ble tablets over a 3-day period would be 11.5 mmol/d,ith a common SD of 4.4 mmol/d. The lower andpper equivalence limits for assessment of the test for-ulation (oral powder) were defined as �20% of the

east squares (LS) mean daily urinary phosphate excre-ion for the reference formulation (chewable tablets)ver the 3-day treatment period. At a significance levelf 0.05 for each of the 1-sided t tests, in a 2 � 2 cross-ver study design assuming an expected treatment dif-erence of 0.3 mmol/d, 23 individuals per treatmentequence would provide a statistical power of 90% forwo 1-sided equivalence tests.

Pharmacodynamic variables were assessed using aixed-effect linear model,19 with fixed effects for se-uence group, period, and formulations; random effector individual within-sequence group; and period base-ine as a covariate. Based on the mixed-effect linearodel, a standard 90% CI was constructed for theifference in LS means of the primary pharmacody-amic variable for oral powder and chewable tablets.n addition, a reference interval was defined as �20%f the LS mean of the primary pharmacodynamic vari-ble for chewable tablets. Pharmacodynamic equiva-ence was claimed if the 90% CI was completely con-ained within the reference interval. This approach wasased on the statistical method for evaluation of aver-ge bioequivalence described in various regulatoryuidelines.20,21

The pharmacokinetic set included individuals fromthe safety set with no major deviations related to intakeof lanthanum carbonate, including all individuals inthe safety set with sufficient postdose blood samplestaken to estimate Cmax and AUC0–48 after dosing onay 4 in all treatment periods. Individuals who vom-ted between dosing and 10 hours postdose on day 4 ofdosing period were excluded from the pharmacoki-etic set.

All pharmacokinetic and related statistical analyses

ere performed by Clinical Data Analysis and Report-

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ing, Covance Clinical Research Unit Ltd (Leeds, UnitedKingdom). Descriptive statistics were determined forplasma lanthanum pharmacokinetic parameters. Thelogarithmically transformed pharmacokinetic parame-ters Cmax and AUC0–48 were compared between for-mulations using a standard mixed-effect linear model.Point estimates and 90% CIs were determined for theratio of LS means for oral powder to chewable tablets.In addition, Tmax was compared between formulationsusing the Wilcoxon signed rank test.

RESULTSSubjects

The study design and subject disposition are shownin Figure 1, and the subject demographic and baselineharacteristics are presented in Table I. Of the 72 in-

dividuals enrolled in the safety set, 56 completed thestudy. Of the 16 individuals who failed to complete thestudy, 14 were excluded from the pharmacodynamicset (n � 53). An additional 5 individuals who com-pleted the study were also excluded from the pharma-

Screening

N = 72

n = 39

Admission

Completed, n = 30Discontinued, n = 9 • Adverse event, 1 • Consent withdraw • Urine collection in • Lost to follow-up,

Oral powder

Chewable tabletn = 33

Completed, n = 30Discontinued, n = 1 • Noncompliance w

R

First dose Last dose Discha

Days25

–3 –2 –1 1 2 3 4 5 6

Figure 1. Study design and subject disposition. In eanum carbonate at 1000 mg/dose (3000 mgof oral powder then chewable tablets, 24 (6(82.1%) in the pharmacokinetic set. Of thethen oral powder, 29 (87.9%) were includpharmacokinetic set. R � randomization.

codynamic set because they failed to eat at least 95% of

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the food during dosing periods. Eight of the noncom-pleters were excluded from the pharmacokinetic set(n � 64). Among the 16 individuals who discontinuedthe study, 6 withdrew consent, 5 were withdrawn dueto incomplete urine collection, 2 were lost to follow-up, 1 discontinued because of an AE, 1 due to noncom-pliance with meals, and 1 because of a protocol viola-tion (intake of prohibited concomitant medication).

Pharmacodynamic AssessmentThe primary study end point was average daily uri-

nary phosphate excretion over the 3 days of treatmentwith lanthanum carbonate. At baseline, mean (SE)daily urinary phosphate excretion was 30.6 (0.87)mmol and 29.4 (0.88) mmol for individuals receivingoral powder and chewable tablets, respectively. The LSmean (SE) daily urinary phosphate excreted after treat-ment with chewable tablets (the reference compound)was 16.8 (0.48) mmol, from which the critical refer-ence range for equivalence was calculated as �3.35mmol. The LS mean (SE) daily urinary phosphate ex-

ete, 4 Completed, n = 30Discontinued, n = 2 • Consent withdrawn, 2

Oral powder

Chewable tablet

ls, 1

Completed, n = 26Discontinued, n = 4 • Protocol violation, 1 • Consent withdrawn, 2 • Urine collection incomplete, 1

n = 56

ut

–3 –2 –1 1 2 3 4 5 6

Admission First dose Last dose Discharge

sing period, individuals received 10 doses of lantha-f the 39 individuals entering the treatment sequence) were included in the pharmacodynamic set and 32

ndividuals entering the sequence of chewable tabletsthe pharmacodynamic set and 32 (97.0%) in the

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creted after treatment with oral powder (the test com-

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pound) was 15.2 (0.48) mmol. The LS mean differencebetween the 2 formulations (oral powder minus chew-able tablets) was calculated as �1.60 mmol. The con-ditions for pharmacodynamic equivalence of oral pow-der and chewable tablets were met because the 90% CIfor the LS mean daily difference (�2.38 to �0.82

mol) lay within the critical reference range of �3.35to 3.35 mmol (Table II). The same analysis was per-formed for a secondary study end point (total urinaryphosphate excretion on day 4). This end point alsosuggested pharmacodynamic equivalence, as the 90%CI for the LS mean difference for oral powder minus

Table I. Demographic and baseline characteristicsof the safety set (N � 72).

Sex, no. (%)Female 20 (27.8)Male 52 (72.2)

Ethnicity, no. (%)White 42 (58.3)Black 26 (36.1)Asian 3 (4.2)Other 1 (1.4)

Age, y 31.4 (8.26)Weight, kg 77.1 (10.02)Height, cm 172.9 (8.81)Body mass index, kg/m2 25.8 (2.45)

Values for baseline characteristics (age, weight, height,and body mass index) are given as mean (SD).

Table II. Analysis of mean daily urinary phosphate excarbonate (pharmacodynamic set).*

Variable

Baseline, mean (SE)Baseline, rangePostdose, LS mean (SE)Postdose, rangeDifference in LS means (90% CI) �1Critical reference range

LS � least squares.*Ten doses of lanthanum carbonate were administered at 1

June 2012

chewable tablets (�2.85 to �0.48 mmol) fell withinthe critical reference range of �3.21 to 3.21 mmol.

Pharmacokinetic AssessmentComparison of the lanthanum pharmacokinetic

profiles of the oral powder and chewable tablet formu-lations was a secondary study end point. For each for-mulation, a time course of mean plasma lanthanumconcentrations after the final dose on day 4 of eachdosing period is shown in Figure 2. LS means for phar-macokinetic parameters, describing bioavailability,with ratios (oral powder:chewable tablets) and 90%CIs, are given in Table III. The pharmacokinetic pro-files show that for both formulations, maximal concen-trations were reached at �4 hours postdose, with in-dividual Tmax values ranging from 0 to 6 hours for theral powder and 0 to 8 hours for the chewable tablets.hen determinable, the arithmetic mean (SD) of t½

values for lanthanum (n � 28 for oral powder, n � 23or chewable tablets) were similar after administrationf either the oral powder (21.9 [2.96] hours) or thehewable tablets (22.3 [3.37] hours), with individualalues in the range of 16.2 to 28.3 hours.

Overall systemic exposure (AUC0–48) was 34%higher for the oral powder than for the chewable tab-lets. The 90% CI for the geometric LS mean ratio(1.26–1.42) did not include unity, indicating that ex-posure to lanthanum on a dose-matched basis wasgreater after administration of the oral powder formu-lation. Between-subject variability in AUC0–48 was dif-ferent for the oral powder and chewable tablets, thearithmetic %CVs for the 2 formulations being 43%and 34%, respectively. Cmax values after administra-

n (mmol) during 3 days of treatment with lanthanum

ral Powder Chewable Tablets

0.6 (0.87) 29.4 (0.88)9 to 43.95 18.27 to 42.79

5.2 (0.48) 16.8 (0.48)6 to 23.22 7.81 to 25.052.38 to �0.82) —

35 to 3.35 —

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tion of the oral powder were 26% higher than for thechewable tablets, without any difference in Tmax, indi-ating that the rate of absorption of lanthanum fromhe oral powder was greater than from the chewable

0.0–0.5 6 12 18 24

Time (h)

30 36 42 48

0.2

0.4

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0.8

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0.9

0.7

0.5

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Figure 2. Change in mean (SD) plasma lanthanumconcentration with time after lanthanumcarbonate treatment as an oral powderor a chewable tablet. Data were colle-cted after administration of the final1000-mg dose of lanthanum carbonate.Blood samples were taken 30 minutesbefore dosing and for the subsequent 48hours.

Table III. Pharmacokinetic parameters after lanthanutablet.

Parameter

Geometric LS

Oral Powder(n � 64)

AUC0–48, ng·h/mL 13.11Cmax, ng/mL 0.60Tmax, h 4*

LS � least squares.*Median.†Difference in median (90% CI).

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ablets. The 90% CI for the geometric LS mean ratioor Cmax (1.20–1.33) did not include unity. Between-ubject variability for Cmax was similar for the 2 for-ulations, with arithmetic %CVs of 38% and 36% for

he oral powder and chewable tablets, respectively.

TolerabilityNo deaths or serious AEs were recorded during the

study. Thirty individuals (41.7%) had �1 TEAE, mostof which were mild. Fewer TEAEs occurred after ad-ministration of the chewable tablets (n � 14 [23.0%])than after the oral powder (n � 23 [32.4%]). Duringreatment with oral powder, 1 individual experiencedbdominal distension and vomiting, which led to dis-ontinuation, although this TEAE was not judged to beelated to the study medication. The difference in thencidence of TEAEs between the 2 formulations wasargely attributable to gastrointestinal disorders (oralowder, n � 13 [18.3%]; chewable tablets, n � 4

[6.6%]); the most common TEAEs were nausea andheadache. A summary of TEAEs occurring in �2 indi-viduals in the safety set is presented in Table IV; allTEAEs are presented in a Supplemental Table in then-line version at http://dx.doi.org/10.1016/j.clinthera.012.05.003.

DISCUSSIONLanthanum carbonate is currently available as a chew-able tablet, but it has recently been reformulated as anoral powder. Different formulations provide patientswith choice and flexibility of administration and aretherefore likely to support good adherence. This study

bonate administered as an oral powder or a chewable

ns

Ratio of Geometric LS Means(90% CI)

able Tabletsn � 58)

9.80 1.34 (1.26–1.42)0.47 1.26 (1.20–1.33)4* 0.01 (0.00–0.05)†

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was conducted with the primary objective of determin-ing whether the new oral powder formulation is phar-macodynamically equivalent to the chewable tabletformulation. As secondary objectives, the pharmaco-kinetic and safety profiles of the 2 formulations werealso compared. The primary analysis of the study (aver-age daily urinary phosphate excretion over a 3-day treat-ment period) suggests that the 2 formulations of lantha-num carbonate were pharmacodynamically equivalent.This conclusion has been accepted by the European Med-icines Agency (see http://mri.medagencies.org/Human/Product/Details/26686 and http://mri.medagencies.org/Human/Product/Details/26685 for decision dates),which has approved the application for marketing autho-rization for lanthanum carbonate oral powder within theEuropean Union.

Systemic exposure was higher for the oral powderthan for the chewable tablets because AUC0–48 andCmax were increased by 34% and 26%, respectively,fter administration of oral powder. The rate of ab-orption of lanthanum was also higher after adminis-ration of oral powder than chewable tablets becausehe elevated Cmax observed after administration of oralowder was reached in the same time (Tmax) as for

Table IV. Treatment-emergent adverse events (TEAE

TEAEs

Oral Powder(n � 71)

No. (%) Events

All TEAEs 23 (32.4) 38Gastrointestinal

Nausea 6 (8.5) 7Upper abdominal pain 3 (4.2) 3Dyspepsia 2 (2.8) 2Gastroenteritis 2 (2.8) 2

Headache 4 (5.6) 5Dizziness 2 (2.8) 2Fatigue 2 (2.8) 2Muscle spasms 1 (1.4) 1

Other TEAEs were recorded, but only those occurring in at lreporting TEAEs after each treatment (oral powder [n � 23individuals reporting AEs (n � 30). This discrepancy is ascperiod because of the crossover design of the study.

hewable tablets. Despite these differences, systemic

June 2012

xposure to lanthanum from both formulations in thistudy was within the range seen in previous pharma-okinetic studies11 of chewable tablets in healthy indi-iduals (Figure 3) and consistent with the very lowbsolute bioavailability (�0.002%) previously re-orted for the chewable tablet.17

As well as this very low bioavailability, the results ofpreclinical studies have indicated that �99.7% of lan-thanum detectable in plasma is bound to plasma pro-teins.22 During toxicologic evaluation in animals, sys-temic lanthanum was deposited at low levels in boneand was excreted by the liver.23 However, no hepato-biliary AEs or increases in serum enzyme activities in-dicative of liver changes have been observed, even inpatients receiving lanthanum carbonate for up to 6years.13 Furthermore, there is no evidence to date thatbone deposition of lanthanum has any adverse ef-fects.24,25 In fact, the incidences of adynamic bone dis-ase and osteomalacia were lower, and bone cell func-ion was improved, in patients treated with lanthanumarbonate compared with those treated with calciumarbonate.24–26 In terms of overall tolerability, �5000

patients with CKD have been involved in clinical stud-ies of lanthanum carbonate. Moreover, long-term tol-

urring in �2 individuals in the safety set.

Chewable Tablet(n � 61)

Overall(N � 72)

No. (%) Events No. (%) Events

14 (23.0) 18 30 (41.7) 56

3 (4.9) 3 8 (11.1) 101 (1.6) 1 3 (4.2) 40 (0.0) 0 2 (2.8) 20 (0.0) 0 2 (2.8) 2

3 (4.9) 3 7 (9.7) 81 (1.6) 1 3 (4.2) 31 (1.6) 1 2 (2.8) 31 (1.6) 1 2 (2.8) 2

individuals overall are summarized. The sum of individualschewable tablets [n � 14]) exceeds the overall number of

to individuals reporting separate TEAEs in each treatment

s) occ

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erability data, including exposure up to 6 years,13 and

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Clinical Therapeutics

clinical experience since first market authorization in2004, have elicited no significant changes to the safetyprofile.

Sixteen individuals failed to complete the study, 13in the oral powder to chewable tablet sequence (Figure1). The reason for this imbalance between the se-quences is not known. The most common reasons fordiscontinuation in this sequence were incomplete urinesample collection (n � 5) and withdrawal of consent(n � 4), both factors apparently unrelated to the treat-ment sequence. There was 1 discontinuation after anAE in this sequence, but this was not judged to betreatment related.

Overall, both formulations were well tolerated.Although there was a difference between the treat-ment groups in the incidence of gastrointestinalevents, these were nonserious in nature and reflectedthose already recognized as common or very com-mon in the European Summary of Product Charac-teristics.27 The overall frequency of gastrointestinalevents observed in the oral powder group (18.3%)was consistent with that seen in a previous Phase Itrial11 at this dose (20%) using the tablet formula-

0.0Study 1 Study 2 Study 3 Study 4 Study 5 Current Study

Study 1 Study 2 Study 3 Study 4 Study 5 Current Study

0.2

0.4

0.6

0.8

1.0A0.9

0.7

0.5

Cm

ax (

ng/m

L)

0.3

0.1

B

05

15

30

4035

2520

AU

C0–

t (ng

•h/m

L)

10

Chewable tabletOral powder

Figure 3. Comparison of arithmetic mean (SD)lanthanum (A) Cmax and (B) AUC0–t

from multiple-dose (1000 mg TID) phar-macokinetic studies (unpublished data,Shire Pharmaceuticals, Basingstoke, Uni-ted Kingdom). Details of studies 1 through5 have been published.11

ion. Nausea, the most common gastrointestinal

1298

vent, was experienced by 8.5% of individuals re-eiving the oral powder, compared with 4% to 20%eceiving tablets in previous Phase I studies.11 There-

fore, the finding of an increased overall frequency ofgastrointestinal TEAEs in the oral powder groupwas not considered clinically important.

The principal, unavoidable limitation of thisstudy was the use of urinary phosphorus excretion asa surrogate pharmacodynamic end point. Homeo-static mechanisms maintain a neutral phosphate bal-ance in healthy individuals, and changes therefore inserum phosphate concentration are not indicative ofthe efficacy of a phosphate binder. The commonlyused method for determining bioequivalence (ie, byusing a drug’s circulating plasma concentration as asurrogate measure of its concentration at the site ofaction) is inappropriate for lanthanum carbonateformulations. The site of action is the lumen of thegastrointestinal tract, and efficacy is therefore inde-pendent of plasma lanthanum concentration. An as-sumption is made that if pharmacodynamic equiva-lence of the formulations is observed in healthyindividuals, it will also be observed in patients withCKD.

CONCLUSIONSIn this multiple-dose study, the oral powder and tab-let formulations of lanthanum carbonate were welltolerated and met the regulatory criteria for pharma-codynamic equivalence in these healthy volunteers.

ACKNOWLEDGEMENTSClinical research was funded by Shire PharmaceuticalDevelopment Ltd. Assay of urinary phosphate wasconducted at Huntingdon Life Science Research(Huntingdon, United Kingdom) under the supervisionof Dr. Richard Abbott, an employee of Shire. Assay ofplasma lanthanum was conducted at Research Trian-gle Institute under the supervision of Dr. Philip Wang,an employee of Shire Pharmaceuticals Inc. Under thedirection of the authors, Drs. Jeremy Bright and PaulFarrow, employees of Oxford PharmaGenesis Ltd,provided writing assistance for this publication. Edito-rial assistance in formatting, proofreading, copyedit-ing, and fact checking was also provided by OxfordPharmaGenesis Ltd. Shire Pharmaceutical Develop-ment Ltd provided funding to Oxford PharmaGenesis

Ltd for support in writing and editing the manuscript.

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D. Pierce et al.

Dr. Pierce was involved in the design of the study,creation of the figures, interpretation of the data, liter-ature searching, and the writing and review of the man-uscript. Mr. Hossack was involved in the analysis andinterpretation of the data and the writing and review ofthe manuscript. Mr. Robinson was involved in the de-sign and conduct of study, interpretation of the data,and writing and review of the manuscript. Dr. Zhangwas involved in the design of the study, analysis andinterpretation of the data and the writing and review ofthe manuscript. Dr. Martin was involved in the designand conduct of the study, interpretation of the dataand the writing and review of the manuscript.

CONFLICTS OF INTERESTDrs. Martin, Pierce, Mr. Robinson, and Dr. Zhang areemployees of Shire Pharmaceuticals Ltd; the authorsalso hold stock in Shire. Mr. Hossack is an employee ofCovance Clinical Research Unit Ltd, who receivedfunding from Shire to conduct the noncompartmentalanalysis of the pharmacokinetic data and the statisticalanalysis and programming of all tables, figures, andlistings based on the pharmacokinetic data.

SUPPLEMENTAL MATERIALSupplemental table accompanying this article can befound in the online version at http://dx.doi.org/10.1016/j.clinthera.2012.05.003.

REFERENCES1. Craver L, Marco MP, Martinez I, et al. Mineral metabolism

parameters throughout chronic kidney disease stages 1-5—achievement of K/DOQI target ranges. Nephrol Dial Trans-plant. 2007;22:1171–1176.

2. Block GA, Port FK. Re-evaluation of risks associated withhyperphosphatemia and hyperparathyroidism in dialysispatients: recommendations for a change in management.Am J Kidney Dis. 2000;35:1226–1237.

3. Kestenbaum B, Sampson JN, Rudser KD, et al. Serumphosphate levels and mortality risk among people withchronic kidney disease. J Am Soc Nephrol. 2005;16:520–528.

4. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabo-lism, mortality, and morbidity in maintenance hemodialy-sis. J Am Soc Nephrol. 2004;15:2208–2218.

5. Kidney Disease: Improving Global Outcomes (KDIGO)CKD-MBD Work Group. KDIGO clinical practice guidelinefor the diagnosis, evaluation, prevention, and treatment ofchronic kidney disease-mineral and bone disorder (CKD-

MBD). Kidney Int. 2009;76(Suppl 113):S1–S130.

June 2012

6. Boaz M, Smetana S. Regression equation predicts dietaryphosphorus intake from estimate of dietary protein intake.J Am Diet Assoc. 1996;96:1268–1270.

7. Shinaberger CS, Greenland S, Kopple JD, et al. Is control-ling phosphorus by decreasing dietary protein intake benefi-cial or harmful in persons with chronic kidney disease? Am JClin Nutr. 2008;88:1511–1518.

8. Daugirdas JT, Finn WF, Emmett M, Chertow GM. Thephosphate binder equivalent dose. Semin Dial. 2011;24:41–49.

9. Martin P, Wang P, Robinson A, et al. Comparison ofdietary phosphate absorption after single doses of lantha-num carbonate and sevelamer carbonate in healthy volun-teers: a balance study. Am J Kidney Dis. 2011;57:700–706.

0. Pierce D, Hossack S, Poole L, et al. The effect of sevelamercarbonate and lanthanum carbonate on the pharmacoki-netics of oral calcitriol. Nephrol Dial Transplant. 2011;26:1615–1621.

1. Pennick M, Poole L, Dennis K, Smyth M. Lanthanumcarbonate reduces urine phosphorus excretion: evidence ofhigh-capacity phosphate binding. Ren Fail. 2012;34:263–270.

2. Sprague SM, Abboud H, Qiu P, et al. Lanthanum carbon-ate reduces phosphorus burden in patients with CKDstages 3 and 4: a randomized trial. Clin J Am Soc Nephrol.2009;4:178–185.

3. Hutchison AJ, Barnett ME, Krause R, et al. Long-termefficacy and safety profile of lanthanum carbonate: resultsfor up to 6 years of treatment. Nephron Clin Pract. 2008;110:c15–c23.

4. Hruska KA, Mathew S, Lund R, et al. Hyperphosphatemiaof chronic kidney disease. Kidney Int. 2008;74:148–157.

5. International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals forHuman Use. Guideline for good clinical practice E6(R1).Federal Register. 1997;62:25691–25709.

6. Burke SK, Slatopolsky EA, Goldberg DI. Renagel®, a novelcalcium- and aluminium-free phosphate binder, inhibitsphosphate absorption in normal volunteers. Nephrol DialTransplant. 1997;12:1640–1644.

7. Pennick M, Dennis K, Damment SJ. Absolute bioavailabil-ity and disposition of lanthanum in healthy human sub-jects administered lanthanum carbonate. J Clin Pharmacol.2006;46:738–746.

8. Riviere JE. Noncompartmental models. In: Riviere JE, ed.Comparative Pharmacokinetics: Principles, Techniques andApplications. 2nd ed. Ames, Iowa: John Wiley & Sons, Ltd;2011:187–206.

9. Patterson S, Jones B. Testing for average bioequivalence.In: Patterson S, Jones B, eds. Bioequivalence and Statisticsin Clinical Pharmacology. Boca Raton, Fla: Chapman &

Hall/CRC; 2006:39–77.

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20. US Department of Health and Hu-man Services, Food and Drug Admin-istration, Center for Drug Evaluationand Research (CDER). Guidance forindustry bioavailability and bio-equivalence studies for orally ad-ministered drug products—generalconsiderations. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf. Ac-cessed February 1, 2012.

21. European Medicines Agency Com-mittee for Medicinal Products forHuman Use (CHMP). Guideline onthe investigation of bioequivalence.http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003011.pdf. Accessed February 1, 2012.

22. Damment SJ, Pennick M. Systemiclanthanum is excreted in the bile ofrats. Toxicol Lett. 2007;171:69–77.

23. Damment SJ, Pennick M. Clinicalpharmacokinetics of the phosphatebinder lanthanum carbonate. ClinPharmacokinet. 2008;47:553–563.

24. D’Haese PC, Spasovski GB, Sikole A,et al. A multicenter study on theeffects of lanthanum carbonate(Fosrenol) and calcium carbonateon renal bone disease in dialysispatients. Kidney Int. 2003;63:S73–S78.

25. Freemont AJ, Hoyland JA, Denton J.The effects of lanthanum carbonateand calcium carbonate on boneabnormalities in patients with end-stage renal disease. Clin Nephrol.2005;64:428–437.

26. Malluche HH, Siami GA, SwanepoelC, et al. Improvements in renal os-teodystrophy in patients treated withlanthanum carbonate for two years.Clin Nephrol. 2008;70:284–295.

27. Shire Pharmaceuticals. Summary ofproduct characteristics (FOSRENOL).http://www.medicines.org.uk/emc/medicine/19617. Accessed February 1,2012.

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Address correspondence to: David Pierce, PhD, Senior Clinical Pharmacol-ogy and Pharmacokinetics Director, Shire Pharmaceutical DevelopmentLtd, Unity Place, Hampshire International Business Park, Chineham,

Basingstoke, RG24 8EP, United Kingdom. E-mail: dpierce@shire.com

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D. Pierce et al.

Supplemental Table. TEAEs occurring in the safety s

Oral Powder(n � 71)

n (%) Even

All TEAEs 23 (32.4) 38Eye disorders 1 (1.4) 1

Dry eye — —Eye irritation 1 (1.4) 1

Gastrointestinal disorders 13 (18.3) 19Abdominal discomfort 1 (1.4) 1Abdominal distension 1 (1.4) 1Abdominal pain 1 (1.4) 1Abdominal pain, upper 3 (4.2) 3Constipation 1 (1.4) 1Diarrhoea 1 (1.4) 1Dry mouth — —Dyspepsia 2 (2.8) 2Epigastric discomfort 1 (1.4) 1Nausea 6 (8.5) 7Vomiting 1 (1.4) 1

General disorders andadministration siteconditions

2 (2.8) 2

Fatigue 2 (2.8) 2

Infections and infestations 3 (4.2) 3Gastroenteritis 2 (2.8) 2Oral herpes 1 (1.4) 1Viral URT infection — —

Musculoskeletal andconnective tissue disorders,

1 (1.4) 1

Muscle spasms 1 (1.4) 1Neck pain — —

Nervous system disorders 6 (8.5) 8Dizziness 2 (2.8) 2Headache 4 (5.6) 5Syncope 1 (1.4) 1

Psychiatric disorders — —Mood altered — —

Reproductive system andbreast disorders, all

— —

Vaginal discharge — —

et.

Chewable Tablet(n � 61)

Overall(N � 72)

ts n (%) Events n (%) Events

14 (23.0) 18 30 (41.7) 561 (1.6) 1 2 (2.8) 21 (1.6) 1 1 (1.4) 1

— — 1 (1.4) 1

4 (6.6) 5 15 (20.8) 24— — 1 (1.4) 1— — 1 (1.4) 1— — 1 (1.4) 1

1 (1.6) 1 3 (4.2) 4— — 1 (1.4) 1— — 1 (1.4) 1

1 (1.6) 1 1 (1.4) 1— — 2 (2.8) 2— — 1 (1.4) 1

3 (4.9) 3 8 (11.1) 10— 1 (1.4) 1

1 (1.6) 1 2 (2.8) 3

1 (1.6) 1 2 (2.8) 3

1 (1.6) 1 3 (4.2) 40 (0.0) 0 2 (2.8) 2

— — 1 (1.4) 11 (1.6) 1 1 (1.4) 1

2 (3.3) 2 3 (4.2) 3

1 (1.6) 1 2 (2.8) 21 (1.6) 1 1 (1.4) 1

4 (6.6) 4 10 (13.9) 121 (1.6) 1 3 (4.2) 33 (4.9) 3 7 (9.7) 8

— — 1 (1.4) 1

1 (1.6) 1 1 (1.4) 11 (1.6) 1 1 (1.4) 1

1 (1.6) 1 1 (1.4) 1

1 (1.6) 1 1 (1.4) 1

(continued)

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Clinical Therapeutics

Supplemental Table (continued).

Oral Powder(n � 71)

Chewable Tablet(n � 61)

Overall(N � 72)

n (%) Events n (%) Events n (%) Events

Respiratory, thoracic andmediastinal disorders

2 (2.8) 2 2 (3.3) 2 4 (5.6) 4

Epistaxis — — 1 (1.6) 1 1 (1.4) 1Oropharyngeal blistering — — 1 (1.6) 1 1 (1.4) 1Oropharyngeal pain 1 (1.4) 1 — — 1 (1.4) 1Rhinitis, allergic 1 (1.4) 1 — — 1 (1.4) 1

Skin and subcutaneoustissue disorders

2 (2.8) 2 — — 2 (2.8) 2

Dry skin 1 (1.4) 1 — — 1 (1.4) 1Rash, papular 1 (1.4) 1 — — 1 (1.4) 1

TEAE � treatment-emergent adverse event. Individuals reporting TEAEs are expressed as a percentage of those in the safety set.The sum of individuals reporting TEAEs after each treatment (oral powder [n � 23] plus chewable tablets [n � 14]) exceeds theoverall number of individuals reporting AEs (n � 30). This discrepancy is ascribed to individuals reporting separate TEAEs ineach treatment period because of the cross-over design of the study.

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