Treating Hyperparathyroidism with Cinacalcet HCl (Sensipar®)
James A. Sloand
Q:
We are currently giving some of our patients on dialysis cinacalcet HCl
(Sensipar®) for the treatment of hyperparathyroidism (HPT). While
we have had good results in reducing parathyroid hormone (PTH) levels,
I am confused about continuing IV vitamin D along with the cinacalcet
HCl. What clinical information is needed to monitor their response to
therapy?
A: The complexities of balancing the many
regulatory functions lost in kidney failure are certainly evident in
the efforts to manage hyperparathyroidism associated with ESRD.
Standard therapy for secondary hyperparathyroidism previously included
dietary phosphorus restriction, calcium and non-calcium based phosphate
binders, and vitamin D analogs. This combination therapy enabled
clinicians to successfully suppress PTH levels to NKF-K/DOQI target
ranges. Unfortun-ately the supraphysiologic dosing of 1,25- dihydroxy
Vitamin D or its analogs required for PTH suppression has frequently
caused intestinal overabsorption of both calcium and phosphorus then
evident in excessive serum levels (Goodman et al., 2000; Sprague,
Llach, Amdahl, Taccetta, & Batlle, 2003). The resulting
hypercalcemia and hyperphosphatemia then require treatment with
additional, costly non-calcium containing phosphate binders. Mechanism of Action
Cinacalcet HCl is a drug that binds to the calcium-sensing receptor in
the parathyroid glands so that less PTH is secreted. In correct doses,
it provides the regulation necessary without the therapy-related risks
of hypercalcemia, hyperphosphatemia, or elevated calcium-phosphate
product. It has proven to be an advantageous monotherapy for patients
on dialysis who have hyperparathyroidism, especially if they are
vitamin D naïve and the serum calcium and phosphate levels are
normal or high. At least two open-label trials have also demonstrated a
desirable reduction in calcium-phosphate product and PTH secretion when
vitamin D is reduced at the time cinacalcet HCl therapy is initiated
(Chertow et al., 2006; Reed et al., 2004).
Concurrent Vitamin D Use
As 1-hydroxylase activity is impaired in renal failure, reducing the
formation of active vitamin D (calcitriol), it is essential that
patients on dialysis continue to receive some vitamin D or its analogs
in order to maintain the integrity of bone, muscle, and cardiovascular
health. Calcitriol also provides a second stimulus to suppress PTH
secretion. However, lower, more physiologic doses of vitamin D or its
analogs should be administered (i.e. intravenous paricalcitol 1-5 ug
three times per week) than previously used. In the future, there may be
an expanded role for vitamin D2 (ergocalciferol) supplementation for
the treatment of secondary hyperparathyroidism as more is learned about
its physiologic effects (Choncol & Scragg, 2007).
Effects on Mineral Metabolism
For patients with PTH levels above K/DOQI targets, cinacalcet HCl
should be started at doses of 30 mg a day given with meals to enhance
absorption. The doses are titrated as needed up to 180 mg/day maximum
dosage. A split dose, twice daily regimen may alleviate nausea, the
most frequent side effect noted at higher doses. For the first month of
therapy, calcium and phosphorous levels should be monitored every 2
weeks, then checked along with PTH levels on a monthly basis.
Hypocalcemia, defined as a corrected calcium level less than 7.5 mg/dL,
occurs in about 5% of treated patients. Hypocalcemia in a patient with
a normal serum phosphate level may require oral calcium
supplementation, perhaps supplanting a non-calcium based phosphate
binder. Concomitant hyperphosphatemia should prompt an increase in the
dose of phosphate binders, and if serum calcium levels are normal to
high as well, a reduction in the dosage of Vitamin D may also be
indicated. Conversely, if both hypocalcemia and hypophosphatemia are
present, vitamin D doses should be increased. Symptomatic hypocalcemia
should prompt immediate reduction in cinacalcet HCl , at least until
symptoms have resolved and steps have been taken to preclude
redevelopment of the problem (i.e. increased Vitamin D or calcium
supplementation). Assessment for symptoms and signs of suggestive of
hypocalcemia is necessary as cinacalcet HCl dosages are adjusted.
Algorithms have been proposed to guide concomitant use of cinacalcet
HCl and vitamin D (Cunningham, 2004).
Medication Interaction
Cinacalcet HCl is hepatically excreted, requiring adjustments for
patients with known liver disease. Individuals with seizure disorders
may incur a greater risk of seizure activity with the use of this drug.
It may also be necessary to adjust dosing of other medications known to
interact with cinacalcet HCl. Tricyclic antidepressant agents may
require dose reduction when used in conjunction with cinacalcet HCl.
Erythromycin or the antifungal agents itracanazole and ketoconazole can
increase cinacalcet HCl levels, mandating close monitoring of serum
calcium levels or reduction in cinacalcet HCl dose.
The most common, transient side effects with initiation of therapy are
nausea/vomiting, headache, and joint/muscle pain (Dong, 2005). Other
rare, varied, and significant side effects have been reported requiring
that clinicians be informed, aware, and sensitive to patient complaints.
Vigilance is recommended in order to manage the complexities of
concurrent cinacalcet HCl and vitamin D therapy for secondary HPT. The
advances in using these agents in individuals with kidney failure
present far more promising outcomes for parathyroid function, bone
integrity, and cardiovascular health.
References
Chertow,
G.M., Blumenthal, S., Turner, S., Roppolo M., Stern L. et al. (2006).
Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active
vitamin D derivatives with controlled PTH and elevated calcium X
phosphate. Clinical Journal of the American Society of Nephrology, 1,
305-312.
Choncol, M. & Scragg, R. (2007). 25-Hydroxyvitamin D, insulin
resistance and kidney function in the Third National Health and
Nutrition Examination survey. Kidney International, 7, 134-139.
Cunningham, J. (2004). Achieving therapeutic targets in the treatment
of secondary hyperparathyroidism. Nephrology, Dialysis and
Transplantation, 19 (Suppl 5) v9-v14.
Dong, B. (2005). An oral calcimimetic agent for the management of hyperparathyroidism. Clinical Therapy, 27, 1725-1751.
Goodman, W.G., Goldin, J., Kuizon, B.D., Yoon, C., Gales, B. 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.
Reed, J., Keightley, G., Blumenthal, S., Bradley C., LaBrecque, J. et
al (2004). The CONTROL STUDY: Enhanced achievement of NKF-K/DOQI bone
metabolism and disease targets using cinacalcet HCl (Sensipar)
[abstract]. Journal of the American Society of Nephrology, 15,
280A-281A.
Sprague, S., Llach, F., Amdahl, M., Taccetta, C., & Batlle, D.
(2003). Paracalcitol versus calcitriol in the treatment of secondary
hyperparathyroidism. Kidney International, 63, 1483-1490.
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