| Abstract|| |
During the recent years, cinacalcet has markedly improved the management of hyperparathyroidism in patients on hemodialysis. However, to the best of our knowledge, there are no specific studies addressing the dose regimen of cinacalcet. The aim of the study was to evaluate the efficacy of cinacalcet on the achievement of targets in the treatment of hyperparathyroidism in two different dosage schedules. Twenty-seven adult patients who were on hemodialysis for more than four months and with severe secondary hyperparathyroidism (intact parathyroid hormone (iPTH) >88 pmol/L) resistant to conventional treatment were included in this prospective study. We used the targets of K/DOQI-clinical guidelines as optimal target of iPTH, calcium and phosphate. Group 1 received a single daily administration of 30 mg of cinacalcet along with the main meal as the starting dose, and the dose was titrated thereafter monthly. Group 2 received cinacalcet with the main meal twice weekly starting with a dose of 90 mg on the first day of the week and 120 mg at midweek and titrated thereafter monthly. The levels of iPTH decreased significantly (P = 0.0001) from 124.00 ± 44.77 pmol/L to 37.78 ± 12.49 pmol/L and from 109.61 ± 53.13 pmol/L to 33.93 ± 12.03 pmol/L after 12 weeks in groups 1 and 2, respectively. After 12 weeks, alkaline phosphatase declined significantly (P = 0.0001) from 143.42 ± 75.20 IU/L to 87.42 ± 14.46 IU/L in group 1 (P = 0.013), and from 148.00 ± 108.49 IU/L to 101.61 ± 46.62 IU/L in group 2 (P = 0.05). There were no significant differences between the reductions of iPTH, calcium phosphate product and alkaline phosphatase levels in both the groups in the vertical comparison at the end of the study. There was no noteworthy difference in side effects between both the groups. Our results indicate that cinacalcet twice weekly is reasonably safe and effective in suppressing high PTH levels in hemodialysis patients, with fewer side effects.
|How to cite this article:|
Al-Hilali N, Hussain N, Kawy YA, Al-Azmi M. A novel dose regimen of cinacalcet in the treatment of severe hyperparathyroidism in hemodialysis patients. Saudi J Kidney Dis Transpl 2011;22:448-55
|How to cite this URL:|
Al-Hilali N, Hussain N, Kawy YA, Al-Azmi M. A novel dose regimen of cinacalcet in the treatment of severe hyperparathyroidism in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2020 Aug 12];22:448-55. Available from: http://www.sjkdt.org/text.asp?2011/22/3/448/80479
| Introduction|| |
Chronic Kidney Disease (CKD) is increasing in prevalence in many parts of the world. CKD is associated with a range of incapacitating complications, including anemia, cardiovascular disease, and secondary hyperparathyroidism. CKD is almost constantly associated with disturbances of calcium and phosphate metabolism. Modification in mineral metabolism and bone structure develop early in the course of CKD and worsen with progressive loss of kidney function. The extent of these modifications may also be influenced by various therapeutic interventions such as vitamin D administration. ,,,
Current treatments of secondary hyperparathyroidism act to either reduce serum phosphorus by dietary restriction and phosphate binders or increase serum calcium by vitamin D administration, which might result in an increase in the calcium/phosphate product , with its subsequent complications. These modalities, while correcting one aspect of mineral metabolism, have a tendency to have adverse effects on others. In recent years, it has become clear that calcium-sensing receptors (CaSR) play a central role in regulating parathyroid hormone (PTH) levels and, subsequently, those of calcium and phosphorus.  Cinacalcet is a calcimimetic agent that acts at the CaSR in the parathyroid gland, increasing the sensitivity of these receptors to serum calcium. This action results in a reduction in PTH secretion that is accompanied by a reduction in serum calcium  . The initial dose of cinacalcet is 30 mg/day which could be increased up to 180 mg/day according to PTH level. ,, Patients are considered to have severe secondary hyperparathyroidism when serum calcium, phosphorus, calcium/phosphorous product and intact parathyroid hormone (iPTH) levels can no longer be adequately controlled by conventional therapy. 
We hypothesized that the intermittent dosage of oral cinacalcet would be as effective as regular dosages in treating secondary hyperparathyroidism in hemodialysis patients. We also thought that the new dose regimen will lower the adverse effects. Under this notion, we conducted a randomized trial in chronic hemodialysis patients with severe secondary hyperparathyroidism (iPTH more than 88 pmol/L).
| Patients and Methods|| |
Twenty-seven adult patients with end-stage renal disease, who had been on maintenance hemodialysis for more than four months, were included in this prospective trial. Eligibility criteria included severe secondary hyperparathyroidism with intact PTH ≥88 pmol/L. All patients were compliant and adequately dialyzed. All patients were refractory to vitamin D derivatives. Patients were considered refractory if iPTH was not reduced to the target, developed hypercalcemia and/or hyperphosphatemia. All patients were recruited from our dialysis unit. Patients were told about the study and informed consent was obtained from all the patients.
Patients with malignancy, active infection, calcium corrected for albumin less than 2.2 mmol/L, diseases causing hypercalcemia, chronic liver disease, pregnancy and concurrent use of medications metabolized by cytochrome P-450 2 D6 were excluded.
All patients were on dialysis treatment three times per week, receiving 12 hours weekly, and four hours per session. Polysulfone dialyzers and bicarbonate bath with dialysate calcium concentration 1.25 mmol/L, sodium concentration of 136 mmol/L were used for dialysis. Blood flow rate was 300 mL/min or more and dialysate flow rate was 800 mL/min. All patients were receiving recombinant erythropoietin intravenously two to three times post dialysis.
The treatment protocol consisted of 4 weeks washout period followed by a treatment period lasting up to 12 weeks. Meanwhile, medical charts of the selected patients were reviewed to extract the basic data, and patients were also interviewed to explain the objective of the study.
Groups and drug titrations
All eligible patients were randomly assigned to two groups. Group 1 (control group) had 14 patients and they received an initial dose of 30 mg of cinacalcet, along with the main meal, as a single daily dose. The dose of cinacalcet was increased every four weeks sequentially to 60 and 90 mg/day if the iPTH value did not get decreased by 50% or more from the baseline value. Group 2 (intervention group) had 13 patients and they received cinacalcet, given with the main meal twice weekly, starting with the initial dose as 90 mg on the first day of the week and 120 mg at midweek (total dose 210/week) and titrated monthly thereafter. If the iPTH value did not get decreased by 50% or more from the baseline, the dose of cinacalcet was increased every four weeks sequentially to 210 mg (total dose 420/week), and 315 mg (total dose 630/week) twice weekly. The active vitamin D derivative dose was maintained at the lowest dose (alfacalcidol 0.25 μg/day) during the study period. The active vitamin D derivative was increased when the patient had a serum Ca level <2.1 mmol/L or patients exhibited symptoms of hypocalcemia.
All symptoms and signs, either observed by the investigators or reported by the subject spontaneously or in response to a direct question, were noted.
We used the targets of K/DOQI-clinical guidelines as optimal target of iPTH, calcium and phosphate.  The dose was adjusted when the mean iPTH level reached 32 pmol/L or less, or if the iPTH declined from the baseline by more than 50%.
Serum albumin corrected calcium, phosphate, alkaline phosphatase and iPTH were measured. The baseline laboratory investigations were measured after randomization of the subjects. Serum albumin corrected calcium, phosphate and alkaline phosphatase were measured weekly. iPTH was measured every four weeks using Coat-A-count immunoradiometric assay method (Diagnostic Products Corporation, Los Angeles, CA, USA).
Study end points
The primary end point was achieving the target iPTH levels while the secondary end point was achieving the target level of corrected calcium, phosphate, calcium/phosphate product, alkaline phosphatase and/or developing severe adverse effects.
| Statistical Analysis|| |
The Statistical Package for Social Sciences (SPSS, Chicago, IL, USA) was used for data processing, using the cut-off level for significance as P ≤ 0.05. The various descriptive statistics (Mean, Standard Deviation) were used to describe the variables. Chi-Square test, independent samples "t" test and paired samples "t" test were used to find the association between two independent variables as appropriate.
| Results|| |
Demographic characteristics of the patients are given in [Table 1]. There was no significant difference in age, gender or the type of renal diseases. Duration on dialysis was significantly longer in group 2. Diabetic nephropathy was the commonest cause of stage 5 renal disease in all the studied patients. Coronary artery disease, cerebrovascular disease, hypertension, dyslipidemia and peripheral arterial disease were the commonly noted co-morbid diseases among our patients. No chronic liver disease was noted among the studied patients. The erythropoietin dose was 4828 ± 2138 and 4723 ± 2100 units/week in groups 1 and 2, respectively.
Laboratory parameters are given in [Table 2]. Notably, albumin corrected calcium was significantly higher in group 2 at the baseline parameters, after eight weeks of treatment. However, calcium/phosphate product was not significantly different during the same period of treatment. Two patients from each group required an increased dose of active vitamin D derivatives because of asymptomatic low calcium. All selected patients were adequately dialyzed with Kt/V more than 1.2.
|Table 2: Albumin corrected calcium, phosphate and calcium phosphate product in both groups.|
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Angiotensin II receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACE-I), β blockers, and calcium channel blockers (CCB) were the preferred anti-hypertensive drugs.
[Figure 1] shows that iPTH declined significantly (P = 0.0001) from 124.00 ± 44.77 pmol/ L to 37.78 ± 12.49 pmol/L, and from 109.61 ± 53.13 pmol/L to 33.93 ± 12.03 pmol/L after 12 weeks in groups 1 and 2, respectively.
|Figure 1: Correlation between intact parathyroid hormone and treatment weeks.|
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[Figure 2] shows that after 12 weeks, alkaline phosphatase declined significantly (P = 0.0001) from 143.42 ± 75.20 IU/L to 87.42 ± 14.46 IU/L in group 1 (P = 0.013), and from 148.00 ± 108.49 IU/L to 101.61 ± 46.62 IU/L in group 2 (P = 0.05). There were no significant differences between the reductions of iPTH, calcium/phosphate product and alkaline phosphatase levels in both the groups in the vertical comparison at the end of the study.
[Table 3] shows the adverse effects in both the groups during the first four weeks. Nausea was commonly seen during the first two weeks and disappeared during the second 2 weeks. In group 2, however, these symptoms were reported only on the day when they received the drug. There were no noteworthy differences in the side effects between both the groups.
|Table 3: Adverse events in both groups during the first 2 weeks and second 2 weeks.|
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| Discussion|| |
Management of secondary hyperparathyroidism in CKD has developed based upon new insights into the pathogenesis and clinical features of this disorder. The 2003 K/DOQI practice guidelines  and The 2009 KDIGO practice guidelines  were developed to provide recommendations for the evaluation and management of chronic kidney disease-mineral and bone disorder (CKD-MBD). These guidelines were formulated in an attempt to minimize the morbidity and mortality associated with abnormal mineral metabolism, abnormal bone processing, possible cardiovascular toxicity, vascular calcification and extra-skeletal calcification associated with the current therapies.
The development of new therapeutic agents that can suppress PTH without exacerbating hyperphosphatemia or causing hypercalcemia is the intention of research into this issue.
The CaSR on parathyroid cells that controls the calcium homeostasis is the primary mechanism regulating secretion of PTH. , The extracellular calcium concentration may also regulate the level of PTH mRNA.  Calcimimetics are agents that allosterically increase the sensitivity of the CaSR in the parathyroid gland to calcium.  Cinacalcet is currently the only available calcimimetic. Prospective studies have found that the addition of cinacalcet to current treatment regimens increases the percentage of patients who are able to attain K/DOQI end-points related to PTH, calcium, and phosphate levels, and the Ca × P product. Numerous prospective randomized studies in patients on maintenance hemodialysis with mild to severe hyperparathyroidism have found that the administration of the calcimimetics produces a dose-dependent reduction in the plasma PTH concentration and a decrease in the levels of calcium and phosphate. ,,,
To the best of our knowledge, there are no specific studies addressing the dose regimen of cinacalcet. Usually, cinacalcet is initiated at a dose of 30 mg/day, with stepwise increments to 60, 90 and 180 mg/day. We conducted this study dividing the patients into two groups, Group 1 taking the standard dosage and Group 2 to whom the drug was administrated in a higher dose, but twice weekly.
Our results showed that the treatment of hemodialysis patients having severe secondary hyperparathyroidism with cinacalcet, was efficacious and well tolerated both among the patients taking the standard dosage and also in those whom the drug was administrated in a higher dose twice weekly. Significant reduction of iPTH to the target level and the calcium/ phosphate product of less than 4.44 mmol 2 /L 2 was achieved in our study. Calcium × phosphate product was also not significantly different in the two groups. Even though the half life of cinacalcet is 30-40 hours,  it seems that pulsing the drug twice weekly is equally effective in making CaSR more sensitive to calcium.
Since all the studied patients were kept on a low dose of active vitamin D derivatives (0.25 μg alfacalcidol tablets/day) symptomatic hypocalcemia was not reported among both the groups. In our study also, cinacalcet, in combination with physiologic or low-dose active vitamin D derivatives, led to an improvement in clinical and biochemical parameters of secondary hyperparathyroidism as has been reported in other studies. ,,
Notably, upper gastrointestinal symptoms were prominent in the first two weeks in both the groups in accordance with what has been reported by others.  However, no significant difference was observed between the two groups. These adverse events markedly decreased by the end of the first month in both the groups.
Compliance to treatment is an important aspect for the effectiveness of any drug. As per observation in this study, those patients who received twice weekly dose were symptomatic only on the day they received cinacalcet. Therefore, twice weekly high dose regime might be a better option among non-compliant patients. In summary, these results indicate that cinacalcet twice weekly is an effective therapeutic intervention that suppresses PTH in patients with severe hyperparathyroidism and has less upper gastrointestinal side effects. In this trial, the number of the selected patients was a limiting factor due to the expanded exclusion criteria in the face of narrow inclusion criteria. Further studies in a large scale are required to confirm the effectiveness of cinacalcet as twice weekly dose.
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Consultant Nephrologist, P.O. Box 22, 6th district, Nasr City 11768, Cairo, Egypt
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]