Cinacalcet

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Cinacalcet

• A calcimimetic agent for hyperparathyroidism
• Khimling Tew
• Surgical Oncology Registrar

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Pharmacology

• Cincalcet hydrochloride binds to the calcium
  sensing receptors of the parathyroid glands and
  increases its sensitivity to extracellular
  calcium
• It increases intracytoplasmic calcium
  concentration in human embryonic kidney cells
  expressing the calcium receptor
• This inhibits the release of PTH and lowers PTH
  levels within a few hours of administration
• Side effects of nausea and vomiting
• Licensed in the U.S. to Amgen and in Asia to
  Kirin Brewery

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Clinical trial

• Reported in April issue of the New England
  Journal of Medicine by Block et al
• Patients with secondary hyperparathyroidism who
  had been on haemodialysis for at least 3 months
  with PTH of at least 300pg/mL (31.8pmol/L) over 3
  readings
• Exclusion criteria infection, cancer,
  hypocalcaemia, concurrent treatment with drugs
  metabolised by cytochrome p450 2D6 which
  cinacalcet inhibits (thioridazine, flecainide,
  most tricyclic antidepressants)

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Trial design

• Randomised stratified for disease severity and
  calcium-phosphorus product
• Double-blind
• Placebo controlled
• Multi-centre 63 sites in North America, 62
  sites across Europe and Australia
• 2 year duration from 2001 to 2003
• 20 of study group could have PTH gt800pg/mL
  (84.8pmol/L)
• PTH measured 24 hours after dosing

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Trial design

• 26 weeks of treatment
• 12 weeks of dose-titration
• 14 weeks of efficacy assessment
• Doses from 30mg daily, increasing every 3 weeks
• Dose increased if PTH gt200pg/mL (21.2pmol/L) and
  calcium 1.95mmol/L
• Dose reduced if PTH lt100pg/mL (10.6pmol/L) on 3
  consecutive visits or if an adverse event occurred

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Trial design

• Phosphate binders used without restriction
• Vitamin D sterols dose increased if PTH increased
  by gt50 from baseline, calcium lt2.1mmol/L or
  symptomatic
• Vitamin D sterols were decreased if
  hypercalcaemic, hyperphosphataemic or PTH
  lt10.6pmol/L on 3 consecutive visits in those
  receiving the lowest daily dose

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End-points

• Primary end-point
• PTH 250pg/mL (26.5pmol/L)
• Secondary end-points
• Reduction in mean PTH of 30 from baseline
• Percent change in PTH, calcium, phosphorus and
  the calcium-phosphorus product

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Results

• 371 patients in treatment arm and 370 in placebo
  group
• Completion of therapy rates were 68 in the
  treatment group and 78 in placebo
• Withdrawal reasons
• Adverse events (15, 7 respectively)
• Withdrawal of consent (4, 3)
• Kidney transplantation (4 each group)
• Death (2 each group)

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Results

• 43 of the treatment group reached the primary
  end-point of PTHlt26.5
• 5 of the placebo group reached the primary
  end-point, plt0.001
• Mean PTH fell by 30 in 64 of treatment vs. 11
  of placebo, plt0.001
• Calcium and phosphorus reduction in the treatment
  group averaged 6.8 and 8.4 respectively,
  plt0.001
• 89 of those who reached the primary end-point in
  the treated group had a reduction in the
  calcium-phosphorus product

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Results

• 91 reported at least 1 adverse event due to
  treatment
• Nausea, not dose related
• Vomiting, dose related
• Withdrawal rate lt5
• Placebo group had more upper respiratory tract
  infections and hypotension

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Discussion

• Cinacalcet has activity over a broad range of
  subject groups
• Longer term trials to determine the effect of
  lowering PTH on cardiovascular outcomes, bone,
  soft tissue calcification and arterial compliance

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Other trials

• Duke University series of 71 haemodialysis
  patients with uncontrolled secondary
  hyperparathyroidism in a dose finding study over
  18 weeks
• Mean PTH decrease of 33 in treatment group vs.
  3 in placebo group, p0.001
• 44 of treated vs. 20 of placebo had PTH
  250pg/mL, p0.029
• 53 vs. 23 had fall in PTH of 30

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Other trials

• 22 patients with primary hyperparathyroidism were
  given cinacalcet for 15 days in a dose finding,
  double-blind RCT
• Decreases in PTH of over 50 occurred within 2-4
  hours after dosing
• Serum calcium normalised on day 1, fall was
  sustained to day 15