Patrick C. D'Haese Faculty of Medicine University of Antwerp, Belgium Controversies in the...

Patrick C. D'Haese Patrick C. D'Haese

Faculty of Medicine Faculty of Medicine University of Antwerp, BelgiumUniversity of Antwerp, Belgium

Controversies in the hyperphosphataemia treatment. Are there alternatives?

Slide show design: Dirk De Weerdt

Introduction (1)Introduction (1)

• Hyperphosphataemia in end-stage renal disease (ESRD) dialysis patients is an important contributor to morbidity and mortality

1.00

1.25

1.50

1.1–4.5 4.6–5.5 5.6–6.5 6.6–7.8 7.9–16.9Serum phosphorus quintile (mg/dL)

Rel

ativ

e m

orta

lity

risk

1.00 1.001.02

1.18*

1.39†

Elevated serum phosphorus increases mortality risk (1)Elevated serum phosphorus increases mortality risk (1)

*P = 0.03; †P < 0.0001 (n = 6407)Note: 1 mmol/L = 3.1 mg/dL

Block GA et al. Am J Kidney Dis 1998;31:607–17.


Rel

ativ

e ris

k of

CV

dea

th

Serum phosphorus concentration (mmol/L)

0.97 1.03 1.00

1.52* 1.55†

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

<1.1 1.1–1.3 >1.81.3–1.5 1.5–1.8

Ref

*P < 0.005; †P < 0.0005 (n = 4544)Note: 1 mmol/L = 3.1 mg/dL

• Nowadays up to 70% of end-stage renal failure patients have hyperphosphatemia• Phosphate control has not improved over the last 2 decades

Achieving multiple K/DOQI targetsAchieving multiple K/DOQI targets

0

10

20

30

40

50

60

PTH Ca × PCa P All 4 targets

70

% o

f pat

ient

s ac

hiev

ing

targ

et

27

5144

8

62 n = 3540

Kim J et al. J Am Soc Nephrol 2003;14:269A.

K/DOQI targets


Rel

ativ

e ris

k of

CV

dea

th

Serum phosphorus concentration (mmol/L)

0.97 1.03 1.00

1.52* 1.55†

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1.80

<1.1 1.1–1.3 >1.81.3–1.5 1.5–1.8

Ref

*P < 0.005; †P < 0.0005 (n = 4544)Note: 1 mmol/L = 3.1 mg/dL

• Nowadays up to 70% of end-stage renal failure patients have hyperphosphatemia• Phosphate control has not improved over the last 2 decades

Achieving multiple K/DOQI targetsAchieving multiple K/DOQI targets

0

10

20

30

40

50

60

PTH Ca × PCa P All 4 targets

70

% o

f pat

ient

s ac

hiev

ing

targ

et

27

5144

8

62 n = 3540

Kim J et al. J Am Soc Nephrol 2003;14:269A.

K/DOQI targets

Control of serum phosphorus levelsControl of serum phosphorus levels

• Aluminum hydroxide

• Calcium acetate, - carbonate

• Magnesium

• Iron dextran - hydroxide

• Sevelamer HCl

• Organic non-calcium, non-aluminum containing phosphate binder

• Has good safety profile

• Lipid lowering effects

• Benificial in the progression of vascular calcifications

• Phosphate binding potency is limited

• Has been associated with acidosis

• Lanthanum carbonate


• Hyperphosphataemia in end-stage renal disease (ESRD) dialysis patients is an important contributor to morbidity and mortality

• Lanthanum carbonate is a new non-calcium, non-aluminium-based phosphate binder that has been shown to effectively control serum phosphate levels in patients with ESRD

• Potent binding

• Selective= Efficacy

Important characteristics of a new phosphate binder

Lowefficacy

Highpill burden

Poorcompliance

The Vicious Cycle of

Low Efficacy

• Low systemic absorptionLow systemic absorption

• Non-toxic at therapeutic dosesNon-toxic at therapeutic doses

• Non-calciumNon-calcium

Lanthanum: the element

• Discovered in 1839 by MosanderDiscovered in 1839 by Mosander

• MW: 139 Da (2 stable isotopes)MW: 139 Da (2 stable isotopes)

• Silvery white, malleable, ductile rare earth element; occurring at Silvery white, malleable, ductile rare earth element; occurring at varying concentrations in terrestrial crust and surface water.varying concentrations in terrestrial crust and surface water.

• Tri-valent cation Tri-valent cation high affinity for phosphate high affinity for phosphate

La3+

CO32-

CO32-

CO32- La3+

PO43-

PO43-

+PO4

3-La3+

PO43-La3+

+

CO32-

CO32-

CO32-

Ks= [La3+][PO43-] = 7.08 x 10-27

= solubility constant


• An extensive development programme has defined specific An extensive development programme has defined specific features of lanthanum carbonate, such as:features of lanthanum carbonate, such as:

• Potency of phosphate bindingPotency of phosphate binding

• Low pill burdenLow pill burden

•High phosphate binding at clinically relevant pH (unlike other High phosphate binding at clinically relevant pH (unlike other agents, effective before phosphate reaches small intestine)agents, effective before phosphate reaches small intestine)

•Reduced requirement for fluid intake with tabletsReduced requirement for fluid intake with tablets

•Independent control of serum phosphate and calcium levelsIndependent control of serum phosphate and calcium levels

•Compatibility with vitamin D supportCompatibility with vitamin D support

• A number of clinical trials have established effective management A number of clinical trials have established effective management of hyperphosphataemia in patients with chronic kidney disease of hyperphosphataemia in patients with chronic kidney disease

(CKD)(CKD)




Damment SJ & Shen V: Clin Nephrol 63: 127-137, 2005










(CKD)(CKD)

In VitroIn Vitro Phosphate- Phosphate-BBinding Profileinding Profile

pH 5pH 5

pH 3pH 3

pH 7pH 7 Ph

osp

ho

rus

Ph

osp

ho

rus

RRem

ove

d (

%)

emo

ved

(%

)

0

20

40

60

80

100

Lanthanumcarbonate

Calciumcarbonate

Calcium acetate Aluminumhydroxide

0

20

40

60

80

100

Lanthanumcarbonate

Calciumcarbonate


0

20

40

60

80

100

Lanthanumcarbonate

Calciumcarbonate


Damment and Webster, Damment and Webster, [Abstract]. J Am Soc Nephrol 2003; 14:204A.[Abstract]. J Am Soc Nephrol 2003; 14:204A.

Stat393

Replacement graphs are attached. Please replace so that the graphs are modifiable. Keep the same axes and legends. Capped title. Removed Phosphate Binding.

Stat393

Changed reference and notes.

Faecal excretion

p.o.p.o.

lanthanum

lanthanum

carbonate

carbonate

ESRD in dialysis

marginal lanthanum intake through

breathing and food

Faecal excretion

NORMAL RF exp.

p.o.p.o.

lanthanum

lanthanum

carbonate

carbonatemarginal lanthanum

intake through breathing and food

Kidneys not involved in excretion (<2% of injected dose)

Gastro-int. abs.

<0.002%Biliary elimination

Metabolism of Lanthanum in Humans

Kidneys not involved in excretionno increased risk for deposition in ESRD

Gastro-int. abs.

<0.002%Biliary elimination

0.0

0.2

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1.6

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6(no dose)

Day 7

24h

Uri

ne

La

Exc

reti

on

(µ

g) Healthy volunteers, multiple La doses

Dose = 1 g lanthanum t.i.d.

Urinary excretion: 0.6-1.0 µg/day

0.0

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Day 1 Day 2 Day 3 Day 4 Day 5 Day 6(no dose)

Day 7

24h

Uri

ne

La

Exc

reti

on

(µ

g) Healthy volunteers, multiple La doses

Dose = 1 g lanthanum t.i.d.

Urinary excretion: 0.6-1.0 µg/day

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0 10 20 30 40 50

Time after dosing (days)

Cu

mu

lati

ve

% d

ose

Faeces Bile Gut transfer Urine

Faeces

Bile

Gut transfer

Urine

La excretion in rats after i.v. LaCl3 (0.3 mg/kg/day)

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Time after dosing (days)

Cu

mu

lati

ve

% d

ose

Faeces Bile Gut transfer Urine

Faeces

Bile

Gut transfer

Urine

La excretion in rats after i.v. LaCl3 (0.3 mg/kg/day)La excretion after single iv LaCl3 (0.3 mg/kg/day)

rats

Behets GJ et al: Curr Opin Nephrol Hypertens 13, 403-409, 2004

Plasma Plasma llanthanum anthanum cconcentrations oncentrations in din dialysis ialysis ppatients atients LLanthanum anthanum ccarbonatearbonate treatment treatment up to 3000 mg/dayup to 3000 mg/dayUSA USA pphase 2 and 3 hase 2 and 3 cclinical linical ttrialsrialsMean+SDMean+SD

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Lanthanum carbonateLanthanum carbonateas a phosphate binderas a phosphate binder










(CKD)(CKD)

Clinical programme: CompletedClinical programme: Completed

Completed Phase II/III studies Completed Phase II/III studies • 202 UK202 UK

• 204 USA204 USA

• 205 USA 205 USA 1-yr safety extension 1-yr safety extension

• 301 Parts I301 Parts I–IV–IV EU EU

• 301 Part V301 Part V–VI–VI EU 2.5-yr safety extension EU 2.5-yr safety extension

• 302 USA302 USA

• 303 EU + SA bone biopsies303 EU + SA bone biopsies

• 307 USA, SA, Poland307 USA, SA, Poland

• 308 USA 308 USA 1-yr safety extension 1-yr safety extension

• 309 USA, EU 309 USA, EU 2-yr safety extension 2-yr safety extension

• 315 Taiwan315 Taiwan

PK/PD, pharmacokinetics/pharmacodynamics;EU, Europe; SA, South Africa

Completed Phase I studiesCompleted Phase I studies• 101 UK101 UK

• 104 UK104 UK

• 105 UK105 UK

• 108 Japan108 Japan

• 109 Japan109 Japan

• 110 UK110 UK

• 111 USA 111 USA PK/PD dialysis patients PK/PD dialysis patients

• 112 UK 112 UK citrate citrate

• 113 UK 113 UK warfarin warfarin

• 114 UK 114 UK digoxin digoxin

• 115 UK 115 UK metoprolol metoprolol

• 116 UK 116 UK bioequivalence bioequivalence

• 117 UK – excretion, i.v.117 UK – excretion, i.v.

• 121 UK121 UK

3000 patients have been enrolled to date (1996–2005); 1700 have contributed to filed studies

Efficacy, safety, tolerability, pharmacokineticsComparison with placebo, calcium-based agents and other commercillay available phosphate binders

SPD405-204: Dose-ranging placebo-controlled trialSPD405-204: Dose-ranging placebo-controlled trial

Intention-to-treat (ITT; n = 144): 112 lanthanum carbonate, 32 placebo;91 patients completed double-blind phase;La = lanthanum carbonate

2-week placeborun-out

Screening

1–3-week placeborun-in

Randomization6-week double-blinded treatment

Placebo, n = 29

La 225 mg/day, n = 29

La 675 mg/day, n = 30

La 1350 mg/day, n = 26

La 2250 mg/day, n = 32

SPD405-204 (USA)SPD405-204 (USA): Evolution of serum phosphate: Evolution of serum phosphate

Difference in serum phosphate between week-in-treatment and end-of-washout (EOW) for all patients randomised

(Mean ± SD)

La 0 mg La 225 mg

La 675 mg

La 1350 mg La 2250 mg

Ch

ang

es

in s

eru

m P

(m

g/d

L)

fro

m E

OW

2

1

0

–1

–2

–3Treatment groups

Week 1Week 2Week 3Week 4Week 5

Week 6

SPD405-204: SummarySPD405-204: Summary

Results for the ITT population (Results for the ITT population (nn = 144) showed that: = 144) showed that:

• Change from baseline analysis identifies > 675 mg as Change from baseline analysis identifies > 675 mg as minimal effective doseminimal effective dose

• Serum phosphate levels are likely to be significantly Serum phosphate levels are likely to be significantly reduced within 2 weeks in patients receiving daily doses reduced within 2 weeks in patients receiving daily doses between 1350 and 2250 mgbetween 1350 and 2250 mg

• Patient compliance was good; overall mean compliance Patient compliance was good; overall mean compliance during the treatment period was 91%during the treatment period was 91%

European (202), USA (302) and Taiwan (315) clinical trials: Study designEuropean (202), USA (302) and Taiwan (315) clinical trials: Study designPlacebo-controlled, double-blind, randomized trials

• Similar inclusion/exclusion criteria

• Starting dose 375 mg/day (Europe) or 750 mg/day USA

• Maximal dose: 3000 mg/day (USA, Taiwan) or 2250 mg/day (Europe)

1–3-weekwashout

4- or 6-week dose titration

Lanthanum carbonate (4 weeks)

Placebo (4 weeks)

Doses of lanthanum carbonate incrementally increased to achieve target serum phosphate levels

Double-blind, parallel-group phase

European study (202)European study (202)

P < 0.0001

Time (weeks)

Titration period (all patients)

Placebo

Lanthanumcarbonate

Hutchison AJ et al. Nephrol Dial Transplant 2004;19:1902–6

–1 0 1 2 3 4 5 6 7 8

8

7

6

5

4

Ser

um

ph

osp

hat

e (m

g/d

L)

Pre-dosing Randomized treatment

Titration phase

Control of serum phosphateControl of serum phosphate European (202), USA (302) and Taiwan (315) clinical trialsEuropean (202), USA (302) and Taiwan (315) clinical trials

• Results demonstrate similar efficacy in different Results demonstrate similar efficacy in different populationspopulations

• Doses of lanthanum translate to low pill burden Doses of lanthanum translate to low pill burden

• New formulations of 750 and 1000 mgNew formulations of 750 and 1000 mg

• 3 pills per day, 1 pill per meal3 pills per day, 1 pill per meal

• Patient compliance was good in all three studiesPatient compliance was good in all three studies

• Mean compliance over double-blind period: Mean compliance over double-blind period:

• 87% (USA)87% (USA)

• 91% (Europe)91% (Europe)

• 95% (Taiwan)95% (Taiwan)

Part 66

months

European study (301): DesignEuropean study (301): DesignProspective, randomized, multicentre, open-label, comparative trial

Weeks of treatment

–3 –1 0 5 25 48 178

Enrollment

Washout

La treatment group (n = 510)

Titration phase

Maintenance phase

Open-label extension

Optional extension phase

Ca treatment group (n = 257)

Part 13

weeks

Part 25

weeks

Part 36

months

Part 46

months

Part 52

years

154

European study (301): European study (301): Serum phosphate levelsSerum phosphate levels

Ser

um

ph

osp

hat

e (m

mo

l/L)

Comparator-controlled trial

1.5

1.0

0.5

0.00

Weeks on treatment

La

Ca

Hutchison AJ. Nephron Clin Pract 2005;100:c8–19; Hutchison et al. Poster presented at the 40th ERA–EDTA World Congress of Nephrology, Berlin, Germany, 2003

2.5

3.0

2.0

3.5

1 2 3 4 5 9 13 17 21 25 29 41 45 4933 37

Modal dose of lanthanum carbonate: 1500 mg/day

Modal dose of calcium carbonate: 3000 mg/day

Switched to La

European study (301): Ca European study (301): Ca P P

Hutchison AJ. Nephron Clin Pract 2005: 100:c8–19

P = 0.961

P = 0.009

P = 0.061

1.0

1.2

1.4

1.6

1.8

2.0

End of titration (Week 5)

Mid-maintenance (Week 17)

End of maintenance (Week 25)

Mea

n C

a x

P r

educ

tion

(mm

ol2 /

L2 )

Study phase

La

Ca

Reduction in incidence of hypercalcaemiaReduction in incidence of hypercalcaemia

• Hypercalcemic episodes (>ULN)

• 6% of lanthanum carbonate-treated patients

• 38% of calcium carbonate-treated patients (P <0.001)

• Hypercalcemia reported as an adverse advent

• 0.4% of lanthanum carbonate-treated patients

• 20.2% of calcium carbonate-treated patients

Hutchison AJ et al. Nephron Clin Pract 2005;100:8–19

US study (307):US study (307):Open-label trial, randomized, parallel group active comparator trial USA, Porto Rico & South-Africa

Screening, then 1–3-week

washout

1–3 weeks 6 weeks 2 years

Standard therapy

Lanthanum carbonate

RandomizationEnd of titration

Finn WF et al. Presented at the 37th Annual Meeting of the ASN, St Louis, MO, USA, 2004

N= 677

N= 682

US study (307):US study (307): Serum phosphate levels Serum phosphate levels (mean ± 95% CI)(mean ± 95% CI)

Finn WF et al. Presented at the 37th Annual Meeting of the ASN, St Louis, MO, USA, 2004

La

Std

Ser

um p

hosp

hate

(m

g/m

L)

Study week Study month

5

6

7

8

1 7 14 26 52 14 18 20 22 240

9

US study (307):US study (307): Median serum PTH levels during the study Median serum PTH levels during the studyS

erum

PT

H (

pg/m

L)

Study week Study month

3 7 26 43 52 14 16 18 20 22 2414

Std

La

Shaded area represents K/DOQI recommended range (150–300 pg/mL);Finn WF et al. Presented at the 37th Annual Meeting of the ASN, St Louis, MO, USA, 2004

100

200

250

0

150

50

300

1

SPD405-309: Long-term control of phosphate levels during lanthanum carbonate SPD405-309: Long-term control of phosphate levels during lanthanum carbonate treatmenttreatment

Ser

um p

hosp

horu

s (m

g/dL

)

0 6 12 18 24 30 36 42 48 54

2

0

4

6

8

Note: 1 mg/dl = 0.32 mmol/LWoods et al. Poster presented at the National Kidney Foundation Clinical Meeting, Washington DC, USA, 2005;

mean (± SD) serum phosphorus levels

Month

10

Lanthanum carbonate: EfficacyLanthanum carbonate: Efficacy

• 1500–3000 mg of lanthanum carbonate reduces serum phosphate levels in the majority of patients

• Treatment has been shown to control serum phosphate levels for up to 5 years

• Similar efficacy in different populations

• Rapidly lowers serum phosphate, without raising serum calcium, offering improved mineral management of ESRD

• Reduced incidence of hypercalcaemia permits optimal use of vitamin D

• Majority of trials to date have used 250- and 500-mg tablets. Use of 750- and 1000-mg tablets will further reduce the pill burden

Most common GI effects in comparative studiesMost common GI effects in comparative studies

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Vomitin

gNau

se

a Diarrh

oea

Consti

patio

n

Per

cent

age

of p

atie

nts

A 6-month study(SPD405-301)

A 1-year study(SPD405-303)

A 2-year study(SPD405-307)

La

Ca

Hutchison AJ et al. Nephron Clin Pract 2005;100:8–19; Torres A et al. Poster presented at the 36th Annual Meeting of the ASN, San Diego, CA, 2003; Data on file

Vomitin

gNau

se

a Diarrh

oea

Consti

patio

n

Vomitin

gNau

se

a Diarrh

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Consti

patio

n

Open-label multicentre Open-label multicentre randomized prospective randomized prospective controlled studycontrolled studyin dialysis patientsin dialysis patients

A total of 98 patients (age 55A total of 98 patients (age 55 ± ±14.314.3 y; y; 59 males)59 males) recruited from various recruited from various dialysis centresdialysis centres in 12 countries. in 12 countries.

In 63 of them a histomorphometric In 63 of them a histomorphometric analysis of baseline analysis of baseline andand follow-up follow-up bone biopsies was performed.bone biopsies was performed.

Patients discontinued: Patients discontinued: Transplantation (n=10)Transplantation (n=10)Death (n=11)Death (n=11)

C. SWAENEPOEL

A. TORRES

A. FERREIRA

A. HUTCHISON

M. DE BROE

M. LAVILLE

H-H. NEUMAYER W. SULOWICZ

S. SULKOVA

A. BALDUCCIG. COEN

L. DJUKANOVICM. POPOVIC

S. PEJANOVIC

A. SIKOLEG. SPASOVSKI

D'Haese PC et al: Kidney Int 63 (S85): 73-78, 2003

Lanthanum carbonateas a phosphate binderLanthanum carbonateas a phosphate binderEffects on bone ?Effects on bone ?

Open-label multicentre randomized prospective controlled Open-label multicentre randomized prospective controlled study in dialysis patients: study in dialysis patients: Study DesignStudy Design

Maximal dose: Lanthanum Carbonate: 3750 mg/dayCalcium Carbonate: 9000 mg/day

D'Haese PC et al: Kidney Int 63 (S85): 73-78, 2003

3025


Lanthanum

n=33

Norm al

Adynam icbone

M ixed

Hyperpara-thyroidism

Baseline

Osteo-m alacia

Norm al

Adynam icbone


One year

M ixed

Osteo-m alacia

Calcium

n=30

Norm al

Adynam icbone

M ixed


Baseline

Osteo-m alacia

Norm al

Adynam icbone


One year

M ixed

Osteo-m alacia

Open-label multicentre randomized prospective controlled study in Open-label multicentre randomized prospective controlled study in dialysis patients:dialysis patients: Results: Categorisation of bone diseaseResults: Categorisation of bone disease

2994D'Haese PC et al: Kidney Int 63 (S85): 73-78, 2003

Long-term lanthanum carbonate treatment does not adversely Long-term lanthanum carbonate treatment does not adversely affect boneaffect bone

• Data have been confirmed in a more recent study showing that compared with calcium carbonate, treatment with lanthanum carbonate for 2 years in patients with ESRD had no adverse effect on bone-cell function and activity

• Higher levels of PTH, osteocalcin and bone-specific alkaline phosphatase in the lanthanum carbonate group suggest an improved bone turnover

• No evidence of aluminum-like effects on bone could be demonstrated in neither study

Behets GJ et al. Kidney Int 67:1830–1836; D'Haese PC, et al. Kidney Int Suppl 2003;85:s73–8;

Malluche et al. Poster presented at the NKF Clinical Meeting, Washington, DC, USA, 2005; Freemont AJ, Denton J. Poster presented at the 41st Congress of the ERA-EDTA, Lisbon, Portugal, May 2004

Lanthanum bone Lanthanum bone concentration after arrest of concentration after arrest of drugdrug1 year treatment1 year treatment,, 22 years follow up years follow up

Spasovski GB et al, submitted 2005

3431


Long-term lanthanum carbonate treatment does not adversely Long-term lanthanum carbonate treatment does not adversely affect boneaffect bone

• Data have been confirmed in a more recent study showing that compared with calcium carbonate, treatment with lanthanum carbonate for 2 years in patients with ESRD had no adverse effect on bone-cell function and activity

• Higher levels of PTH, osteocalcin and bone-specific alkaline phosphatase in the lanthanum carbonate group suggest an improved bone turnover

• No evidence of aluminum-like effects on bone could be demonstrated in neither study

Behets GJ et al. Kidney Int 67:1830–1836; D'Haese PC, et al. Kidney Int Suppl 2003;85:s73–8;

Malluche et al. Poster presented at the NKF Clinical Meeting, Washington, DC, USA, 2005; Freemont AJ, Denton J. Poster presented at the 41st Congress of the ERA-EDTA, Lisbon, Portugal, May 2004

Lanthanum bone Lanthanum bone concentration after arrest of concentration after arrest of drugdrug1 year treatment1 year treatment,, 22 years follow up years follow up

Spasovski GB et al, submitted 2005

3431


No evidence of toxicityNo evidence of toxicity

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6

Years on Treatment

Bo

ne

La

nth

an

um

(u

g/g

) w

et

wt.

Highest concentrationtested in animals (90ug/g)

No Toxicity

15 year projectionAll absorbed drug into bone

No clearance (46ug/g)

Damment et al, 2004. JASN, 15, 271A (Abstract F-P0948). Studies LAM-IV-301, LAM-IV-303 and LAM-IV-307

Bone lanthanum levels in treated ESRD patients


Localization of Aluminum in Osteomalacic BoneLocalization of Aluminum in Osteomalacic Bone

AluminonAluminon®® Staining Staining

Principle of X-ray fluorescence

ESRF - The European Synchrotron Radiation Facility, Grenoble

Typical X-ray fluorescence spectrum of bone sample

Behets GJ et al: Kidney Int 67: 1830-1836, 2005

Extremely low La levels require sensitive detection methods Extremely low La levels require sensitive detection methods

Deposition of lanthanum Deposition of lanthanum in bonein bone

Normal boneNormal bone

Lanthanum is located on the outer edge of calcified boneLanthanum is located on the outer edge of calcified bone


Behets GJ et al: Kidney Int 67: 1830-1836, 20053275

Rats loaded with 2000 mg/kg/day lanthanum carbonate for 12 weeksRats loaded with 2000 mg/kg/day lanthanum carbonate for 12 weeks

Lanthanum localization is independent of the presence or Lanthanum localization is independent of the presence or amount of osteoid, in animals with a mineralization defectamount of osteoid, in animals with a mineralization defect

3275Behets GJ et al: Kidney Int 67: 1830-1836, 2005

Rats loaded with 2000 mg/kg/day lanthanum carbonate for 12 weeksRats loaded with 2000 mg/kg/day lanthanum carbonate for 12 weeks


LaLa

LaLa

LaLa

LaLa

LaLa

LaLa

LaLa

LaLa

LaLaLaLa

LaLa

LaLa

LaLa

LaLa

LaLa

Possible mechanisms of lanthanumPossible mechanisms of lanthanum deposition in bone deposition in bone

3212


Lanthanum deposition in bone couldnot be associated with a specific ultrastructural localization nor could it be associated with a particular bone lesion

Conclusions (1)Conclusions (1)

• Extensive pre-clinical and clinical trial programme

• Data from over 3000 patients treated with lanthanum carbonate

• Lanthanum carbonate has been shown to be a potent phosphate binder

• Effectively reduced serum phosphate levels in patients with ESRD

• Selective phosphate binder

• Greater phosphate-binding affinity compared to calcium and sevelamer

• Effective at clinically relevant pH range

• Lanthanum carbonate has a simple dosage regimen

• Wide range of tablet sizes available(250, 500, 750 and 1.000 mg)

• Low pill burden, as little as one tablet with each meal(3.000 mg/day or 2.250 mg/day)

Conclusions (2)Conclusions (2)

• Low systemic absorption

• Not renally excreted

• No effect of ESRD on plasma lanthanum exposure

• Deposition in bone and liver is limited. No clearcut evidence for toxic effects established so far

• Excellent non-clinical and clinical safety profiles

• Lanthanum treatment significantly reduced incidence ofhypercalcemia AEs

21/04/23

Aluminum and Lanthanum in the human bodyAluminum and Lanthanum in the human body

Aluminum Lanthanum

Phosphate binding +++ +++

Gastrointestinal absorption ++ +

Renal elimination +++ ±

Biliary elimination + +++

Interference hematopoiesis ++ –

Bone toxicity ++ –

Hypoparathyroidism + –

Encephalopathy +–

Patrick C. D'Haese Faculty of Medicine University of Antwerp, Belgium Controversies in the...

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