FOSFORO, DIALISI PERITONEALE E CKD-MBD
Nuove prospettive terapeutiche
Maurizio Gallieni
U.O. Nefrologia e Dialisi
Ospedale San Carlo Borromeo
Milano
Ringraziamenti
• Gds Dialisi Peritoneale
• Comitato organizzatore locale
• Dr. Sergio Bove - Osp. Montichiari (BS)
• Genzyme
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
Caratteristiche ideali di un chelante del P
- 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 gastrointestinale variabili
- Flessibilità di formulazione (compresse, sciroppo,
bustine)
- Palatabile (migliora la compliance)
- Economico
Chelanti tradizionali
• Sali di alluminio
• Sali di calcio
• Sali di magnesio
Chelanti di seconda
generazione
• Sevelamer HCl
• Lantanio Carbonato
Nuove prospettive
Nuove prospettive
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•
•
•
•
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)
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,2
Alan Slade,2 Robert Schmouder.2
1Denver Nephrology, PC, Denver, CO; 2Novartis Pharmaceuticals Corp, East Hanover, NJ.
J Am Soc Nephrol 19: 2008
F-PO1801
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)
Livelli di P
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)
J Am Soc Nephrol 20: 2009
TH-P0615
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)
Am J Physiol Renal Physiol 242: F447-F452, 1982;
Nicotinamide restores phosphaturic effect of PTH and calcitonin in phosphate
deprivation
T. 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 intestine
K 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
Fosforo
7.0
6.0
5.0
Vol 23: 562-567
Vol 23: 562-567
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)
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 pazienti
Sevelamer 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 pazienti
Sevelamer 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
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)
AMG 223, a Novel Polymer-Based Treatment for Hyperphosphatemia,
Ameliorates Hyperphosphatemia and Secondary Hyperparathyroidism
in 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
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
•
•
•
•
•
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)
WARF: P06053US
A 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: P06053US
A 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: P06053US
A 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.