Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1), Available online through

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1 Research Article ISSN: Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1), Available online through Comparison of efficacy and safety of Cinacalcet versus Calcitriol in patients of secondary hyperparathyroidism in Indian population. *Amol K Choulwar 1, Ashish A Mungantiwar 2, Meena Chintamaneni 3 1 R & D Center, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai , Maharashtra, India. 2 R & D Center, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai , Maharashtra, India. 3 School of Pharmacy and Technology Management, Narsee Monjee Institute of Management & Higher Studies, Vile Parle (west), Mumbai , Maharashtra, India Received on: ; Revised on: ; Accepted on: ABSTRACT Treatment of secondary hyperparathyroidism with vitamin-d and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetic agents (Cinacalcet) act on the calciumsensing receptor and lower parathyroid hormone (PTH) levels without increasing calcium and phosphorus levels. We report the results of our comparative, open, randomized and prospective clinical trial conducted in Indian population evaluating the effectiveness and safety of cinacalcet hydrochloride. Patients with chronic kidney disease (CKD) and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (28 patients) or calcitriol (20 patients) for 24 weeks. Once-daily doses of cinacalcet were increased from 30 mg to 180 mg to achieve PTH levels of 250 pg per milliliter or less. The primary end point was decrease in the PTH levels (The percent change from base line) of patients at the end of treatment. Mean PTH level in patients treated with Cinacalcet was significantly decreased from pg/ml to pg/ml (i.e %) and from pg/ml to pg/ml (i.e %) in Calcitriol treated patients at the end of treatment. Also Mean Serum calcium level in patients treated with Cinacalcet was decreased from 8.83 mg/dl to 8.07 mg/dl (i.e. 8.61%) and from 8.76 mg/dl to 8.72 mg/dl (i.e. 0.46%) in Calcitriol group. Cinacalcet effectively reduced PTH levels independently of disease severity or changes in vitamin D sterol dose and improves calcium phosphorus homeostasis in CKD patients who have uncontrolled secondary hyperparathyroidism. Keywords: Secondary Hyperparathyroidism, Cinacalcet, Calcitriol, Parathyroid Hormone, Chronic Kidney Disease. INTRODUCTION: Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease, affecting most of those who are receiving hemodialysis. [1, 2] The disorder is characterized by persistently elevated levels of parathyroid hormone and complicated by important disturbances in mineral metabolism. [3] Bone disease is the most widely recognized consequence of secondary hyperparathyroidism. [4] Several reports indicate, however, that alterations in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism or the therapeutic measures used to manage it, contribute to soft-tissue and vascular calcification, cardiovascular disease, and the risk of death. [5-10] Episodes of hypercalcemia and hyperphosphatemia are often aggravated by the use of large doses of calcium as a phosphate-binding agent, particularly in combination with vitamin D sterols, which increase the absorption of calcium and phosphorus. [10-13] Conventional management of SHPT includes the provision of active vitamin-d derivatives and phosphate binders (Ca and non Ca-based). Although active vitamin D derivatives are effective in reducing PTH levels, their use may exacerbate hypercalcemia and hyperphosphatemia as a result of enhanced intestinal Ca and P absorption. [32] *Corresponding author. Amol Choulwar Dy.Manager-Medical Services R & D Center, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai , Maharashtra, India Tel.: amolchoulwar@gmail.com Therefore, despite the use of phosphate binders and active vitamin D derivatives, the majority of hemodialysis patients fail to achieve all four targets (PTH, Ca, P, and the Ca-P product [Ca _ P]) recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines. [33,34] There is thus considerable interest in identifying therapeutic alternatives that control secondary hyperparathyroidism while limiting these side effects. The calcium-sensing receptor regulates the secretion of parathyroid hormone. [14] Calcimimetic agents increase the sensitivity of the calciumsensing receptor to extracellular calcium ions. [15,16] Inhibit the release of parathyroid hormone, and lower parathyroid hormone levels within a few hours after administration. [17-19] Calcimimetics bind to the Ca-sensing receptor, a G protein coupled receptor that is present on the parathyroid gland. [35] The calcimimetics, such as cinacalcet HCl, allosterically modulate the Ca-sensing receptor, increasing its sensitivity to extracellular Ca and thereby decreasing PTH synthesis and secretion from the parathyroid gland. [36,37] Cinacalcet reduces PTH with simultaneous decreases in both serum concentrations of Ca and P. [38,39] This mechanism of action differs fundamentally from that of vitamin-d sterols, which diminish the transcription of the parathyroid hormone gene and hormone synthesis over a period of many hours or several days. [20] Results of small clinical trials indicate that the calcimimetic agent cinacalcet hydrochloride not only reduces parathyroid hormone levels but also lowers serum calcium and phosphorus levels in patients with secondary hyperparathyroidism. [21-23] Calcitriol is the most active known form of vitamin D3 is act on parathyroid gland & in stimulating intestinal calcium transport. Calcitriol has been shown to stimulate intestinal calcium absorption.

2 Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1), In order to determine whether Cinacalcet provides a therapeutic advantage to Calcitriol, this open, randomized, prospective, phase III study in Indian patients with Secondary hyperparathyroidism was undertaken. Here, we report the results of phase-iii clinical trial of Cinacalcet Versus Calcitriol in Indian patients with Secondary hyperparathyroidism. MATERIALS AND METHODS: Study candidates were patients in medically stable condition with secondary hyperparathyroidism who were 18 years of age or older and were Predialysis patients suffering from CKD. The primary eligibility criterion was a mean plasma parathyroid hormone level of at least 200 pg per milliliter, established by measurements obtained within a screening period. Also patients with Serum calcium >7.1 mg/ml and <11.0 mg/dl, Serum phosphorus > 2.5 mg/dl and Patients willing to provide informed consent to be included in the study. Exclusion criteria included evidence of cancer, active infection, diseases known to cause hypercalcemia, or a serum calcium level below 8.4 mg per deciliter (2.1 mmol per liter), corrected for albumin. Because cinacalcet can inhibit cytochrome P-450 2D6, patients were excluded if they were receiving drugs such as flecainide, thioridazine, and most tricyclic antidepressants, which have a narrow therapeutic index and are metabolized by this enzyme. Also Pregnant or Lactating females, Female Patient with childbearing age not using medically approved contraceptives, Patient with known suspected history of hypersensitivity to Cinacalcet, Patients with impaired liver function, defined as SGOT or SGPT > 2.0 times the upper limit of normal and Patients with unstable clinical condition were excluded from the study. The study protocols were reviewed and approved by the institutional review board at each study site, and written informed consent was obtained from each patient before enrollment. The complete data set was held at the Macleods Pharmaceuticals Ltd. Statistical analyses and data interpretation were conducted in biostatistics department at Macleods Pharmaceuticals Ltd. The investigators had unrestricted access to the primary data and were not limited by the sponsor with regard to statements made in the final article. Study Design Comparative, open, randomized and prospective clinical trials were conducted at three sites in India. Patients were randomly divided into two groups. Each patient as per randomization was received either group A (Cinacalcet) or group B (Calcitriol) for a period of 24 weeks. Assessment of Safety Post-Study Examination Physical examination, Clinical examination and pathology laboratory tests were performed to cater to the post study safety assessments at the end of visit-7. Patients Monitoring During the Study During each follow-up visit i.e. on week4, week8, week12, week16, week 20 and week 24 vital signs & clinical examinations was carried out. Assessment of vital signs could also be done, if the principle investigator finds it necessary at any time during the conduct of the study. In case of any abnormality in vital signs, abnormal pathology lab reports or any adverse events observed during the study, principle investigator could take the decision whether the patients would be continued in the study or not. Study End Points Assessment of Clinical Efficacy I) Clinical Efficacy was graded as follows: a] Improved: Improvement in signs and symptoms at the end of therapy. b] Failure: Either worsening or no improvement of signs and symptoms at the end of therapy. II) Decrease in the PTH levels (The percent change from base line). III) Decrease in the calcium, phosphorus and calcium X phosphorus at the end of treatment (The percent change from base line). Patient Dropout Patients who have not completed the therapy were considered as drop out cases. The reason for the drop out was properly recorded in CRF. Statistical Analysis Data was analyzed using appropriate statistical test such as z- test, ANOVA and Chi-Square test. The value of p<0.05 was considered as statistically significant. The values of efficacy parameters were presented as Mean ± SD. Base-line laboratory measurements were obtained and patients characteristics were noted during the screening period. Mean values for parathyroid hormone, calcium, phosphorus, and the calcium phosphorus product during the efficacy-assessment phase were calculated with the use of all available results from each patient. RESULTS: Total 50 patients were enrolled in the study and were randomly assigned to receive cinacalcet (28 patients) or Calcitriol (22 patients). The initial dose of cinacalcet is 30 mg (once a day), Increased sequentially every four weeks to 60, 90, 120 & 180 mg once daily and Clacitriol is 0.25 mcg daily, May be increased by 0.25 mcg daily at intervals of 4-8 weeks. The dose was reduced if parathyroid hormone levels were less than 100 pg per milliliter (10.6 pmol per liter) on three consecutive study visits or if patients reported an adverse event requiring. Dose adjustments were permitted at four-week intervals during the efficacy assessment phase. Patients were allowed to continue receiving vitamin-d sterols during this study if they were prescribed. Therefore, guidance was provided for changes in the dose of vitamin-d. Patients were also permitted to continue to receive phosphate-binding agents and participate in this study. Increases in the dose of vitamin D sterols were permitted if parathyroid hormone levels rose by 50 percent or more from base line. Biochemical Determinations Plasma parathyroid hormone levels and serum calcium and phosphorus levels were measured at each study visit. Biochemical measurements were made at central reference laboratory. I) Demographic Characteristics Mean age of the patients was years for Cinacalcet treated group and for Calcitriol treated group. Average weights of the patients were Comparable. The mean weight of patients was kg & respectively. Out of 50 patients, 35 patients were males and the remaining 15 were females. A total of 50 patients were enrolled in the study. II) Drop Outs and Managements There were two patients drop out from Calcitriol group. All 48 patients completed the study were included for statistical analysis. III) Baseline Characteristics The mean body temperature was F for patients on Cinacalcet therapy & F for patients on Calcitriol therapy at basal and F and F temperature at the end of study in Cinacalcet and Calcitriol group respectively. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean body temperature did not show any significant changes in both the groups. The mean pulse-rate was 81.05/min for patients of Cinacalcet therapy and

3 75.58/min for patients of Calcitriol therapy at basal. At the end of therapy pulse-rate was 82.00/min and 76.91/min for patients of Cinacalcet therapy and Calcitriol therapy, respectively. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean pulse-rate did not show any significant changes in both the groups. The average respiratory rate was 17.10/min for patients of Cinacalcet therapy & 16.33/min for patients of Calcitriol therapy at basal. At the end of treatment, the respiratory rate was found to be18.94/min for patients of Cinacalcet therapy & 18.75/min for patients of Calcitriol therapy. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean respiratory rate did not show any significant changes in both the groups. The average Blood Pressure of patients treated with Cinacalcet was / mmhg and /78.00 mmhg of patients treated with Calcitriol at basal & /84.89 mmhg of Cinacalcet group and131.09/83.27 mmhg of patients with Calcitriol treated group after the 24 week treatment. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean blood pressure did not show any significant changes in both the groups. IV) Efficacy Parameters Primary end point was achieved and following parameters were recorded a) PTH Levels: Mean PTH level for patients treated with Cinacalcet tablet was significantly decreased from pg/ml to pg/ml (i.e %) at the end of treatment. In the same line there was significant decreased PTH level from pg/ml to pg/ml (i.e %) for patients treated with Calcitriol tablet at the end of treatment. There was no statistically difference (p>0.05) for PTH level between the groups at the end of therapy. Table 1. Base-line demographic characteristics of patients (Group-A) (Group-B) No. of Patients Age (yrs)* ± ±12.82 Weight (Kg)* 55.25± ±13.26 Sex Male Female 6 9 p > 0.05 there was no statistical significant difference between the two groups.* By z-test (age & weight)± values = mean ± SD Table 2. Comparison of patients examination between two groups Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1), Table 3. Comparison in biochemical parameters between two groups Mean PTH Level Base Line (pg/ml) ± ± End of Therapy (pg/ml) ± ± Percent Change 24.64% 21.63% Mean Serum Calcium Level Base Line (mg/dl) 8.83 ± ± 0.45 End of Therapy (mg/dl) 8.07 ± ± 0.66 Percent Change 8.61% 0.46% Mean Serum Phosphorus Level Base Line (mg/dl) 4.65 ± ± 1.41 End of Therapy (mg/dl) 5.70 ± ± 1.26 Percent Change % -2.60% Calcium-Phosphorus Ratio Base Line ± ± End of Therapy 31.02± ± Percent Change -5.22% -0.09% z-test (between two groups)± values = mean ± SD Table 4. Global assessment of treatment by patients for efficacy Excellent Efficacy Number of Patients (%) 19 (67.86%) 06 (30.00%) Good Efficacy Number of Patients (%) 08 (28.57%) 11 (55.00%) Poor Efficacy Number of Patients (%) 01 (03.57%) 03 (15.00%) Chi-Square test PTH Level (pg/ml) Base Line End of Therapy Mean Body Temperature Base Line ( 0 F) ± ± 1.68 End of Therapy ( 0 F) 98.9 ± ± 1.3 Mean Pulse Rate Base Line (per minute) ± ± 7.66 End of Therapy (per minute) ± ± 5.45 Mean Respiratory Rate Base Line (per minute) ± ± 0.84 End of Therapy (per minute) ± ± 0.86 Mean Blood Pressure (Systolic) Base Line (mm Hg) ± ± End of Therapy (mm Hg) ± ± Mean Blood Pressure (Diastolic) Base Line (mm Hg) ± ± End of Therapy (mm Hg) ± ±6.92 z-test (between two groups)± values = mean ± SD 0 Cinacalcet Calcitriol Figure 1: Comparison of PTH Level between Baseline and End of Therapy values b) Serum Calcium Levels: Mean Serum calcium level for patients treated with Cinacalcet tablet was decreased from 8.83 mg/dl to 8.07 mg/dl (i.e. 8.61%) at the end of treatment. After the treatment with Calcitriol tablet decreased from 8.76 mg/dl to 8.72 mg/dl (i.e. 0.46%). There was no statistically difference (p>0.05) in serum calcium level between the groups at the end of therapy. c) Serum Phosphorus Levels: The mean serum phosphorus levels in patients treated with Cinacalcet was increased from 4.65mg/dL to 5.70mg/dL (i.e %) at the end of therapy and after the treatment with Calcitriol from 4.9 mg/dl to 5.03 mg/dl (i.e. 2.6%).

4 Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1), d) Calcium X Phosphorus Level: The mean change in calcium x phosphorus level for patients treated with Cinacalcet tablet was increased from to (i.e 5.22%) at the end of therapy. Similarly there was comparable increased in calcium x phosphorus level after the treatment wit Calcitriol tablet from to (i.e. 0.09%). V) Laboratory Investigations The comparison of laboratory parameters hemoglobin, CBC, SGOT, SGPT, serum creatinine level, BUN, serum uric acid level, were done for both groups at basal & at the end of treatment. There were no statistically difference (p>0.05) during and after the treatment, within the group. DISCUSSION: Our results indicate that cinacalcet effectively reduces parathyroid hormone levels in patients with secondary hyperparathyroidism who are receiving hemodialysis and ameliorates disturbances in serum calcium and phosphorus that have been associated with adverse clinical outcomes. The use of vitamin D sterols to lower parathyroid hormone levels, particularly in combination with calcium-containing phosphate binders, can cause hypercalcemia and hyperphosphatemia by promoting intestinal absorption of calcium and [24, 25, 26, 27] phosphorus. These disturbances often interrupt treatment, leading to inadequate biochemical control and progression of bone disease. [26, 28] Such derangements are also associated with an increased risk of death, increased arterial stiffness, and calcification of the coronary arteries, aorta, and cardiac [8, 9, valves ] Thus, the fact that cinacalcet lowers parathyroid hormone levels while reducing serum calcium and phosphorus levels represents a potentially important therapeutic development. The study concluded that, patients treated with Cinacalcet show more improvement in the clinical efficacy parameters than Calcitriol. There were no serious adverse effects found throughout the study. Thus, Cinacalcet has the potential to reduce the prevalence of hyperparathyroidism and limit the potential toxicity of current treatment strategies. This study provides evidence that, Cinacalcet may clinically relevant pharmacologic approach to improve the Secondary hyperthyroidism symptoms and controling associated disturbances in mineral metabolism in patients who receive peritoneal dialysis (PD) or Hemodialysis (HD). ACKNOWLEDGEMENT The authors gratefully acknowledge Dr. Rajendra Agarwal, Managing Director, Macleods Pharmaceuticals Ltd for providing the necessary facilities. REFERENCES: 1. Salem MM. Hyperparathyroidism in the hemodialysis population: a survey of 612 patients. Am J Kidney Dis, 29, 1997, Owda A. Elhwairis H, Narra S, Towery H, Osama S. Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren Fail, 25, 2003, Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. 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