FOSFORO, DIALISI PERITONEALE E CKD-MBD

Nuove prospettive terapeutiche

Maurizio Gallieni U.O. Nefrologia e DialisiOspedale San Carlo BorromeoMilano

• Gds Dialisi Peritoneale

• Comitato organizzatore locale

• Dr. Sergio Bove - Osp. Montichiari (BS)

• Genzyme

Ringraziamenti

Cardini della terapia dell'iperfosfatemia

• Dialisi • Dieta• Chelanti del fosforo

Treated patients (n=3186) were matched with untreated (n=3186) by their baseline serum phosphate levels and propensity score of receiving phosphate binder during the first 90 d

- Efficace: alta capacità chelante (bassa dose, con ridotto numero di compresse)

- Non tossico, senza effetti collaterali e con assorbimento sistemico assente

- Capacità chelante mantenuta a valori di pH gastro-intestinale variabili

- Flessibilità di formulazione (compresse, sciroppo, bustine)

- Palatabile (migliora la compliance)

- Economico

Caratteristiche ideali di un chelante del P

Chelanti tradizionali• Sali di alluminio• Sali di calcio• Sali di magnesio

Chelanti di seconda generazione

• Sevelamer HCl• Lantanio Carbonato

Nuove prospettive

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

Chelanti a base di ferro

- Struttura polinucleare, con basso prodotto di solublità fosforo – ferro trivalente

- Assorbimento sistemico minimo (comunque utile in dialisi)

- Efficaci su ampio range di pH

PA21 (VIFORPharma)

PA21 is intended to be used particularly in hemodialysis patients. Regulatory filling is anticipated in 2011.

SBR 759 (NOVARTIS)Dati preliminari presentati ASN 2008

SBR759: Efficacy of a Novel Phosphate Binder in Dialysis Patients GeoffreyBlock,1 Ahmed Amer,2 Stephanie Brillhart,1 Thomas Dumortier,2 Jochen Klupp,2Alan Slade,2 Robert Schmouder.2 1Denver Nephrology, PC, Denver, CO; 2Novartis Pharmaceuticals Corp, East Hanover, NJ.

F-PO1801J Am Soc Nephrol 19: 2008

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

Livelli di P

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

TH-P0615J Am Soc Nephrol 20: 2009

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

Am J Physiol Renal Physiol 242: F447-F452, 1982;

Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate deprivationT. J. Berndt, J. D. Pfeifer, F. G. Knox, S. A. Kempson and T. P. Dousa

Nicotinamide inhibits sodium-dependent phosphate cotransport activity in rat small intestineK Katai, H Tanaka, S Tatsumi, Y Fukungaga, K Genjida, K Morita, N Kuboyama, T Suzuki, T Akiba, K Miyamoto and E Takeda

Nephrology Dialysis Transplantation, Vol 14, Issue 5 1195-1201, Copyright © 1999

7.0

6.0

5.0

Fosforo

Vol 23: 562-567

Vol 23: 562-567

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

Fosforo (media pesata):Sevelamer carbonato: 4.6 ± 0.9 mg/dl Sevelamer HCl: 4.7 ± 0.9 mg/dl

P nei limiti KDOQI (3,5-5,5 mg/dl):Sevelamer carbonato: 71% dei pazientiSevelamer HCl: 70% dei pazienti

Bicarbonati:Sevelamer carbonato: +1.3 ± 4.1 mmol/l (p<0.001) Sevelamer HCl: invariato

Studio cross-over 4+4 settimane – 31 pazienti ED

3: 1125-1130, 2008

3: 1125-1130, 2008

3: 1125-1130, 2008

Fishbane S, et al. A randomized, parallel, open-label study to compare once-daily sevelamer carbonate powder dosing with thrice-daily sevelamer hydrochloride tablet dosing in CKD patients on hemodialysis. Am J Kidney Dis. 2010; 55(2): 307-15.

Calo del fosforo:Sevelamer carbonato x 1/die: 2.0 ± 1.8 mg/dl (da 7.3 mg/dl) Sevelamer HCl x 3/die: 2.9 ± 1.3 mg/dl (da 7.6 mg/dl)

P nei limiti KDOQI (3,5-5,5 mg/dl):Sevelamer carbonato x 1/die: 54% dei pazientiSevelamer HCl x 3/die: 64% dei pazienti

Effetti collaterali: simili nei due gruppi (ma sevelamer carbonato ha mostrato in questo studio maggior tendenza a nausea, vomito e sospensione trattamento)CONCLUSIONI (MG): singola dose giornaliera è efficace ma non vantaggiosa

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

AMG 223, a Novel Polymer-Based Treatment for Hyperphosphatemia,Ameliorates Hyperphosphatemia and Secondary Hyperparathyroidismin a Chronic Renal Failure Model XunXiang Du, Jon Mills, Jamie Cope, Marcus Fischer, Lawrence Lee, Jill Kohler, Jerry Buysse. Ilypsa Inc., SantaClara, CA.

This study evaluated the impact of a new polymer-based phosphate binder AMG 223 on hyperphosphatemia, secondary hyperparathyroidism and parathyroid gland (PTG) hyperplasia in a rat model of chronic renal failure (CRF). CRF was induced by 5/6th subtotal nephrectomy and adriamycin injection (NADR). AMG 223 (3, 5 and 7% wt/wt) treatment significantly (p<0.01) reduced sP vs untreated NADR into the normal range on day 14. AMG 223 at 3 and 7% decreased P significantly (p<0.05) versus untreated NADR at day28

AMG 223 treatment caused decreased trends in serum PTH, PTG areas, and decreased proliferation vs untreated NADR

In a rat model of CRF, AMG 223 reduced P, PTH, parathyroid cell proliferation and parathyroid gland enlargement

J Am Soc Nephrol 20: 2009 F-PO1862

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

• Sali di ferro• Sali di ferro e magnesio• Associazione Mg e Ca• Nicotinamide• Resine

– Sevelamer carbonato– AMG 223– MCI-196 (Colestimide o Colestilan)

• Chitosano (chewing gum)• Dendrimero: P06053US (WARF)

Nuove prospettive

WARF: P06053USA New Phosphate Binder for Blocking Phosphate Absorption and Reducing Hyperphosphatemia

INVENTORS • Hector DeLuca, Katarzyna Barycka, Katie Williams

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing methods and compositions for controlling serum phosphate levels in mammals.

P06053US consists of dendrimers, which are highly branched, symmetric molecules

WARF: P06053USA New Phosphate Binder for Blocking Phosphate Absorption and Reducing Hyperphosphatemia

INVENTORS • Hector DeLuca, Katarzyna Barycka, Katie Williams

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing methods and compositions for controlling serum phosphate levels in mammals.

- The compositions consist of dendrimers, which are highly branched, symmetric molecules. - Dendrimers are well known therapeutic tools, although dendrimers that bind phosphate were not known previously. - The dendrimer compositions of this invention may include a hydrochloride, hydrobromide, hydroacetate or other hydroanionic form. 

WARF: P06053USA New Phosphate Binder for Blocking Phosphate Absorption and Reducing Hyperphosphatemia

INVENTORS • Hector DeLuca, Katarzyna Barycka, Katie Williams

The Wisconsin Alumni Research Foundation (WARF) is seeking commercial partners interested in developing methods and compositions for controlling serum phosphate levels in mammals.

- Prevents the absorption of more than 50% of the phosphate in the GI tract - More versatile, cheaper and effective on a weight basis than the most commonly used phosphate binder - Dendrimer composition is soluble. - These compositions successfully decreased serum phosphate levels in rats.