1	Calcimimetics in the Management of Renal Osteodystrophy Driving the CaR to Achieve the NKF K/DOQI Bone Metabolism and Disease Guidelines
2	Traditional Therapies: Potential Mechanisms for PTH Reduction
3	NKF K/DOQI Targets PTH, Ca, P, and Ca × P Product
4	Dialysis Patients Need Improved Control of Their PTH Levels
5	K/DOQI Bone & Mineral CPGs DOPPS Data
6	K/DOQI Bone & Mineral CPGs Gambro Data
7	K/DOQI™ Targets for PTH and Ca × P Are Associated with Mortality: FMC Data
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9	Type 2 Calcimimetic NPS R-586 / AMG 073 Cinacalcet HCl = Sensipar
10	Calcimimetics Bind Allosterically to Membrane-spanning Regions of CaR
11	Cinacalcet HCl: Pharmacodynamics Summary Rapid onset of action—PTH levels declined within 30–60 minutes after oral administration Extent of PTH reduction was largely dose-dependent Maximum effect on PTH secretion occurred approximately 2–6 hours post-dose Therapeutic effect of lowering PTH is ~ 24 hours
12	Single Dose of Cinacalcet Results in Dose-dependent Reduction in PTH in Dialysis Patients
13	Cinacalcet HCl: Pharmacokinetics Summary Absorption Well absorbed Administration with food increases bioavailability Distribution Highly protein bound (97%) Large volume of distribution Metabolism Metabolized predominantly by hepatic microsomal enzymes Inhibits CYP2D6 Elimination Terminal half-life 30–40 hours Steady state achieved within 7 days Not dialyzable
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15	Methods Trial Design Parallel studies: NA and AUS/EUR Dec 20, 2001 to Jan 16, 2003 Enrollment: NA (410) ; AUS/EUR (331) Randomization Cinacalcet (371) Placebo (370)
16	Methods Trial Participants Inclusions Adults w/ thrice-weekly HD for ³ 3 mo PTH ³ 300 pg/mL x 3 Ca²⁺ ³ 8.4 mg/dL Stable Vit.D &/or Phosphate binder, if prescribed Exclusions Cancer, infection Drugs metabolized by P-450 2D6 Flecainade, thioridazine, lithium, TCA
17	Methods Trial Design Randomized, double-blind, placebo-controlled Study duration: 26 weeks Phase 1: 12-wk titration Phase 2: 14-wk efficacy-assessment Dose adjustments: 30, 60, 90, 120, 180 mg/d Initial dose 30 mg/d, adjusted q 3 wk in phase 1, and q 4 wk in phase 2 Increased if I-PTH > 200, S.Ca ≥ 7.8 Reduced if I-PTH < 100 on 3 consecutive visits, or S.E. occurred Standard care of 2° HPT
18	Methods Trial Design
19	Use of Concomitant Medications
20	Methods Lab Parameters Ca/P/PTH q-study visit pre-dialysis - Weekly during dose-titration - Bi-weekly during efficacy-assessment Bone-specific alkaline phosphatase (BSAP) at wks 0 and 26
21	Methods End Point Analyses Primary: Proportion with mean I-PTH £ 250 pg/mL during efficacy-assessment phase Secondary: - Proportion with ³ 30% PTH decrease - Percent change of Ca/ P/ I-PTH/ (Ca × P)
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36	Cinacalcet Summary Targets the CaR, the dominant regulator of PTH production Greater achievement of K/DOQI targets than currently achievable Can be used with all other agents to achieve K/DOQI targets Monitoring should be done periodically as with any other intervention
37	Calcimimetics in the Treatment of HPTH Reversible “chemical parathyroidectomy” Inhibit PTH secretion Inhibit PTH synthesis Inhibit PTH gland proliferation (hyperplasia) No development of tolerance Lower Ca, P, and product Can cause intermittent changes in PTH levels
38	Vit D Sterols vs Cinacalcet CaR allosteric effector (cell surf.) ↓ Ca × P product Oral Rapid onset (minutes) and short duration of action (hours to days) Effects external to PTH gland PTH recycling Inhibits PTH synthesis, secretion VDR ligand (genomic receptor) ↑ Ca × P product Oral or parenteral Slow onset and long duration of action (days to weeks) Effects external to PTH gland No PTH recycling Inhibits PTH synthesis
39	Questions ?