|
The Role of Cinacalcet in Treating Secondary Hyperparathyroidism
| The Issues in Renal Nutrition
in Nephrology Nursing department is designed to focus on nutritional
issues for nephrology patients. Address correspondence to: Susan Reams,
Department Editor, Nephrology Nursing Journal; East Holly Avenue/Box
56; Pitman NJ 08071-0056; (856) 256-2320. The opinions and assertions
contained herein are the private views of the contributors and do not
necessarily reflect the views of the American Nephrology Nurses'
Association. |
The challenge for clinicians to manage secondary hyperparathyroidism
(HPT) and improve patient outcomes is apparent in light of a
continuously growing dialysis population. Eventually, nearly all
patients on maintenance dialysis will develop secondary HPT. The
magnitude of this problem is evidenced by the complications associated
with secondary HPT, including renal osteodystrophy, vascular and
soft-tissue calcification, and increased risk of morbidity and
mortality (Rostand & Drueke, 1999; Bro & Olgaard, 1997).
Limitations of Traditional Therapies
When
the National Kidney Foundation(NKF) K/DOQI Clinical Practice Guidelines
for Bone Metabolism and Disease in Chronic Kidney Disease (CKD) were
published in October 2003, the only therapies available to treat
secondary HPT were diet, phosphate binders, and Vitamin D sterols (NKF,
2003). Due to the limitations of these therapies, meeting the tighter
target ranges for the four HPT indicators (see Table 1) did not seem
feasible. An observational analysis of the U.S. Dialysis Outcomes and
Practice Patterns Study (DOPPS) database revealed that, over a 12-month
period, only 1% of dialysis patients met all four K/DOQI parameters for
secondary HPT when treated with diet, phosphate binders, and Vitamin D
sterols alone (Kim et al., 2003).
Calcium
balance is an issue of concern due to findings of accelerated vascular
calcification in dialysis patients (Goodman, et al., 2000). Calcium
balance is affected by calcium containing phosphate binders, dialysate
calcium level, and dietary calcium intake. In addition, although
Vitamin D sterols have been shown to work well to suppress parathyroid
hormone (PTH), they often cause hypercalcemia and elevated
calcium-phosphorus product (Ca x P) (Martin & Gonzalez, 2001;
Slatopolsky et al., 1984). There is also evidence to suggest that the
incidence of adynamic bone disease and calcific uremic arteriolopathy
(calciphalaxis) are on the rise due to high doses of calcitriol in
combination with calcium based phosphate binders (Coates, 1998; Hruska,
1998; Goodman et al., 1994).
A Novel Approach to Secondary HPT
With
the introduction of cinacalcet (SensiparJ) in April 2004, another
treatment option for secondary HPT is now available. Cinacalcet is a
first in class calcimimetic drug that works to directly inhibit PTH in
patients with CKD stage 5. The calcium-sensing receptor (CaR) located
on the chief cell of the parathyroid gland regulates PTH secretion in
response to serum calcium levels (Brown, 2000). Cinacalcet increases
the sensitivity of the CaR to directly inhibit PTH secretion (Goodman
& Turner, 2002). In contrast, Vitamin D inhibits PTH production and
increases intestinal absorption of calcium, which indirectly decreases
PTH secretion (Martin & Gonzalez, 2001). Cinacalcet works rapidly,
within 30-60 minutes, to reduce serum PTH levels. Maximum reduction in
PTH occurs approximately 2 to 6 hours post dose and PTH levels
stabilize in 1 week. PTH levels should be drawn at least 12 hours after
oral administration of cinacalcet to ensure the most accurate reading
(Amgen, 2004).
Efficacy of Cinacalcet
In
three phase-3 clinical trials, cinacalcet effectively lowered PTH while
simultaneously lowering calcium, phosphorus, and Ca x P. This
improvement of all four HPT indicators was statistically significant.
Cinacalcet allows significantly more patients to reach the K/DOQI
target ranges versus control subjects on traditional therapies alone
(Moe et al, 2003).
Cinacalcet has been shown to significantly lower PTH and Ca x P levels
in patients on dialysis with secondary HPT disease ranging from mild to
severe (Block et al., 2004; Quarles et al., 2003). A 30% or greater
reduction in PTH was seen in over 60% of patients receiving cinacalcet
versus placebo groups. (Block et al., 2004). Cinacalcet also
worked to lower PTH with or without Vitamin D, making it possible to
use cinacalcet as a first line of therapy (Goodman, et al., 2003). It
should be noted, however, that the biological importance of Vitamin D
should not be overlooked, and it is imperative to correct Vitamin D
deficiency in the CKD population.
Drug Safety and Side Effects
Cinacalcet
is safe to use in patients with intact PTH greater than 300 pg/mL and
serum calcium 8.4 mg/dL or greater (Amgen, 2004). Cinacalcet does not
have to be held for elevated Ca x P. Since cinacalcet lowers serum
calcium, it is possible for hypocalcemia to occur. In the event of
hypocalcemia (serum Ca less than 8.4 mg/dl), adding or increasing
calcium supplementation, calcium-based phosphate binders, and/or
Vitamin D may be considered to increase serum calcium. If serum Ca
falls below 7.5 mg/dl or symptoms of hypocalcemia persist, and if
Vitamin D cannot be increased, then cinacalcet should be withheld. When
Ca improves to greater than 8.0 mg/dl and/or symptoms of hypocalcemia
are resolved, it is recommended to restart cinacalcet at the next
lowest dose. Patients with a history of seizure disorder may use
cinacalcet with careful monitoring of serum calcium levels or symptoms
associated with hypocalcemia.
The
most prominent side effects noted were nausea and vomiting, which were
usually temporary and mild to moderate in severity (Block et al.,
2004). In 90% of these cases only one or two isolated episodes of
nausea or vomiting were reported (Data on file, Amgen, 2004). In the
event of a severe episode of nausea or vomiting, cinacalcet should be
held and the therapy can be resumed when GI symptoms subside. If nausea
or vomiting persists, lowering the dose of cinacalcet is generally
effective in alleviating this problem.
Dosing Guidelines
Cinacalcet
is available in 30 mg, 60 mg, and 90 mg tablets, and the maximum dose
is 180 mg. Initial dosing of cinacalcet is 30 mg per day, independent
of the severity of PTH elevation. Upon initiation of cinacalcet, PTH
should be repeated in 1 month and serum calcium and phosphorus levels
should be measured within 1 week. Dosing adjustments follow a
sequential step titration based on PTH response until the desired PTH
goal is achieved. The maintenance dose depends on the severity of
secondary HPT and the desired PTH target.Taking cinacalcet with meals
enhances bioavailability by 50% to 80% and improves GI tolerance. The
best time for patients on hemodialysis to take the drug is with the
first meal following their dialysis treatment. This will ensure that
serum PTH is measured at least 12 hours post dose to obtain a
consistently reliable PTH result.
Summary
Compelling
evidence exists to use cinacalcet as a primary therapy for the
treatment of secondary HPT in patients requiring dialysis. The
benefits of directly lowering PTH in combination with improving
calcium-phosphorus homeostasis provide a means to better achieve the
K/DOQI bone guidelines. Cinacalcet is usually well tolerated and safe
to use, making it possible to treat a wide range of patients with
varying levels of disease severity. The ideal course of action for this
novel therapy is for nephrology nurses and renal dietitians to use a
team approach in the management of secondary HPT.
References
Amgen. (2004). SensiparJ (cinacalcet Hcl), prescribing information. Thousand Oaks, CA: Amgen.
Bro, S., & Olgaard, K. (1997). Effects
of excess PTH on nonclassical target organs. American Journal of Kidney
Disease, 30, 608-620.
Block, G.A., Martin, K.J., de Francisco,
A.L.M., Turner, S.A., Avram, M.M., Suranyi, M.G., et al. (2004).
Cinacalcet for secondary hyperparathyroidism inpatients receiving
hemodialysis. New England Journal of Medicine, 350, 1516-1525.
Brown, E.M. (2000). Calcium receptor and
regulation of parathyroid hormone secretion. Reviews in Endocrine &
Metabolic Disorder, 1, 307-315.
Coates, T., Kirkland, G.S., Dymock,
R.B.,Murphy, B.F., Brealey, J.K., Mathew, T.H., Disney, A.P. (1998).
Cutaneous necrosis from calcific uremic ateriolopathy. American Journal
of Kidney Disease, 32, 348-391.
Goodman, W.G., Fadda, G.Z., Finkelstein,
F.O., Mittman, N., Lien, Y.H., Leblanc, M., et al. (2003). Cinacalcet
HCl is an effective primary therapy for the management of secondary
hyperparathyroidism (abstract). Journal of he American Society of
Nephrology, 14, 460A.
Goodman WG, Goldin J, Kuizon BD, Yoon C,
Gales B, Sider D, et al. (2000). Coronary-artery calcification in young
adults with end-stage renal disease who are undergoing dialysis. New
England Journal of Medicine, 342, 1478-1483.
Goodman W.G., Ramirez J.A., Belin T.R.,
Chon Y., Gales B., Segre G.V., Salusky I.B. (1994). Development of
adynamic bone in patients with secondary hyperparathyroidism after
intermittent calcitriol therapy. Kidney International, 46, 1160-1166.
Goodman, W.G., & Turner, S.A. (2002).
Future role of calcimimetics in end stage renal disease. Advances in
Renal Replacement Therapy, 9, 200-208.
Hruska, K. (1998). New concepts in renal osteodystrophy. Nephrology, Dialysis, and Transplantation, 13, 2755-2760.
Kim, J., Pisoni, R.I., Danese, M.D., Satayathum, S., Klassen, P., &
Young, E.W. (2003). Achievement of proposed NKF-K/DOQI bone metabolism
and disease guidelines: results from the dialysis outcomes and practice
patterns study (DOPPS). Journal American Society of Nephrology, 14,
269A-270A.
Martin, K.J. & Gonzalez, E.A. (2001).
Vitamin D analogues for the management of secondary hyperparathryoidsm.
American Journal of Kidney Disease, 38(Suppl. 5), S34-S40.
Moe, S.M., Coburn, J.W., Quarles, L.D.,
Goodman, W.G., Chertow, G.M., Block, G.A., Drueke, T., Cunningham, J.,
Sherrard, D.J., McCary, L.C., Olson, K.A., Turner, S.A., Martin, K.J.
(2003). Achievement of proposed NKF-K/DOQI bone metabolism and disease
targets: treatment with cinacalcet HCL in dialysis patients with
uncontrolled secondary hyperparathyroidism (abstract). Journal of the
American Society of Nephrology, 14, 48A.
National Kidney Foundation (NKF). (2003).
NKF-K/DOQI Clinical Practice Guidelines for bone metabolism and disease
in chronic kidney disease. American Journal of Kidney Disease, 42
(Suppl. 3), S1-S201.
Quarles, L. D., Sherrard, D. J., Adler, S.,
Rosansky, S. J., McCary, L. C., Liu, W., Turner,S.A., and Bushinsky, D.
A. (2003). The calcimimetic AMG 073 as a potential treatment for
secondary hyperparathyroidism of end-stage renal disease. Journal of
the American Society of Nephrology, 14, 575 - 583.
Rostand, S.G., & Drueke, T.B. (1999).
Parathyroid hormone, vitamin D, and cardiovascular disease in chronic
renal failure. Kidney International, 56, 383-392.
Slatopolsky, E., Weerts, C., Thielan, J.,
Horst, R., Harter, H., & Martin, K.J. (1984). Marked suppression of
secondary hyperparathyroidism by intravenous administration of
1,25-dihydrozycholecalciferol in uremic patients. Journal of Clinical
Investigation, 74, 2136-2143.
|
