Comparison of Efficacy and Safety of Cinacalcet Versus Calcitriol in Patients of Secondary Hyperparathyroidism in Indian Population

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Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1),38-42 Research Article Available online through ISSN: 0974-6943 www.jpronline.info Comparison of efficacy and safety of Cinacalcet versus Calcitriol in patients of secondary hyperparathyroidism in Indian population. *Amol K Choulwar1, Ashish A Mungantiwar2, Meena Chintamaneni3 1R & D Center, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai-400093, Maharashtra, India. 2R & D Center, Macleods Pharmaceuticals Ltd, G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai-400093, Maharashtra, India. 3School of Pharmacy and Technology Management, Narsee Monjee Institute of Management & Higher Studies, Vile Parle (west), Mumbai-400 056, Maharashtra, India Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011

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 calcium- sensing 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 404.43 pg/ml to 304.74pg/ml (i.e. 24.64%) and from 495.09 pg/ml to 387.99 pg/ml (i.e. 21.63%) 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 Therefore, despite the use of phosphate binders and active vitamin D de- chronic kidney disease, affecting most of those who are receiving hemodi- rivatives, the majority of hemodialysis patients fail to achieve all four tar- alysis.[1, 2] gets (PTH, Ca, P, and the Ca-P product [Ca _ P]) recommended by the The disorder is characterized by persistently elevated levels of parathyroid National Kidney Foundation Kidney Disease Outcomes Quality Initiative hormone and complicated by important disturbances in mineral metabo- (K/DOQI) clinical practice guidelines.[33,34] lism.[3] There is thus considerable interest in identifying therapeutic alternatives Bone disease is the most widely recognized consequence of secondary that control secondary hyperparathyroidism while limiting these side ef- hyperparathyroidism.[4] Several reports indicate, however, that alterations fects. The calcium-sensing receptor regulates the secretion of parathyroid in calcium and phosphorus metabolism, as a result of either secondary hormone.[14] Calcimimetic agents increase the sensitivity of the calcium- hyperparathyroidism or the therapeutic measures used to manage it, con- sensing receptor to extracellular calcium ions.[15,16] Inhibit the release of tribute to soft-tissue and vascular calcification, cardiovascular disease, and parathyroid hormone, and lower parathyroid hormone levels within a few the risk of death.[5-10] hours after administration.[17-19]

Episodes of hypercalcemia and hyperphosphatemia are often aggravated Calcimimetics bind to the Ca-sensing receptor, a G protein–coupled recep- by the use of large doses of calcium as a phosphate-binding agent, particu- tor that is present on the parathyroid gland.[35] The calcimimetics, such as larly in combination with vitamin D sterols, which increase the absorption cinacalcet HCl, allosterically modulate the Ca-sensing receptor, increasing of calcium and phosphorus.[10-13] its sensitivity to extracellular Ca and thereby decreasing PTH synthesis and secretion from the parathyroid gland.[36,37] Cinacalcet reduces PTH with Conventional management of SHPT includes the provision of active vita- simultaneous decreases in both serum concentrations of Ca and P. [38,39] min-D derivatives and phosphate binders (Ca and non–Ca-based). Although active vitamin D derivatives are effective in reducing PTH levels, their use This mechanism of action differs fundamentally from that of vitamin-D may exacerbate hypercalcemia and hyperphosphatemia as a result of en- sterols, which diminish the transcription of the parathyroid hormone gene hanced intestinal Ca and P absorption. [32] and hormone synthesis over a period of many hours or several days.[20]

*Corresponding author. Results of small clinical trials indicate that the calcimimetic agent cinacalcet Amol Choulwar hydrochloride not only reduces parathyroid hormone levels but also lowers Dy.Manager-Medical Services serum calcium and phosphorus levels in patients with secondary hyperpar- R & D Center, Macleods Pharmaceuticals Ltd, athyroidism.[21-23] G-2, Mahakali Caves Road, Shanti Nagar, Andheri-East. Mumbai-400093, Calcitriol is the most active known form of vitamin D3 is act on parathyroid Maharashtra, India gland & in stimulating intestinal calcium transport. Calcitriol has been shown Tel.: + 91-8976028284 to stimulate intestinal calcium absorption. E-mail: [email protected]

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 38-42 Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1),38-42 In order to determine whether Cinacalcet provides a therapeutic advantage Assessment of Safety to Calcitriol, this open, randomized, prospective, phase III study in Indian patients with Secondary hyperparathyroidism was undertaken. Here, we Post-Study Examination report the results of phase-III clinical trial of Cinacalcet Versus Calcitriol in Physical examination, Clinical examination and pathology laboratory tests Indian patients with Secondary hyperparathyroidism. were performed to cater to the post study safety assessments at the end of visit-7. MATERIALS AND METHODS: Study candidates were patients in medically stable condition with second- Patients Monitoring During the Study ary hyperparathyroidism who were 18 years of age or older and were During each follow-up visit i.e. on week4, week8, week12, week16, week Predialysis patients suffering from CKD. The primary eligibility criterion 20 and week 24 vital signs & clinical examinations was carried out. was a mean plasma parathyroid hormone level of at least 200 pg per milliliter, established by measurements obtained within a screening period. Also Assessment of vital signs could also be done, if the principle investigator patients with Serum calcium >7.1 mg/ml and <11.0 mg/dl, Serum phospho- finds it necessary at any time during the conduct of the study. In case of rus > 2.5 mg/dl and Patients willing to provide informed consent to be any abnormality in vital signs, abnormal pathology lab reports or any included in the study. adverse events observed during the study, principle investigator could take the decision whether the patients would be continued in the study or not. Exclusion criteria included evidence of cancer, active infection, diseases known to cause hypercalcemia, or a serum calcium level below 8.4 mg per Study End Points deciliter (2.1 mmol per liter), corrected for albumin. Because cinacalcet can Assessment of Clinical Efficacy inhibit cytochrome P-450 2D6, patients were excluded if they were receiv- I) Clinical Efficacy was graded as follows: ing drugs such as flecainide, thioridazine, and most tricyclic antidepres- a] Improved: Improvement in signs and symptoms at the end of therapy. sants, which have a narrow therapeutic index and are metabolized by this b] Failure: Either worsening or no improvement of signs and symptoms at enzyme. Also Pregnant or Lactating females, Female Patient with child- the end of therapy. bearing age not using medically approved contraceptives, Patient with known II) Decrease in the PTH levels (The percent change from base line). suspected history of hypersensitivity to Cinacalcet, Patients with im- III) Decrease in the calcium, phosphorus and calcium X phosphorus at the paired liver function, defined as SGOT or SGPT > 2.0 times the upper limit end of treatment (The percent change from base line). of normal and Patients with unstable clinical condition were excluded from the study. Patient Dropout Patients who have not completed the therapy were considered as drop out The study protocols were reviewed and approved by the institutional cases. The reason for the drop out was properly recorded in CRF. review board at each study site, and written informed consent was obtained from each patient before enrollment. Statistical Analysis Data was analyzed using appropriate statistical test such as z- test, ANOVA The complete data set was held at the Macleods Pharmaceuticals Ltd. and Chi-Square test. The value of p<0.05 was considered as statistically Statistical analyses and data interpretation were conducted in biostatistics significant. The values of efficacy parameters were presented as Mean ± department at Macleods Pharmaceuticals Ltd. The investigators had unre- SD. stricted access to the primary data and were not limited by the sponsor with regard to statements made in the final article. Base-line laboratory measurements were obtained and patients’ characteristics were noted during the screening period. Mean values for parathyroid Study Design hormone, calcium, phosphorus, and the calcium–phosphorus product dur- Comparative, open, randomized and prospective clinical trials were con- ing the efficacy-assessment phase were calculated with the use of all avail- ducted at three sites in India. Patients were randomly divided into two able results from each patient. groups. Each patient as per randomization was received either group A (Cinacalcet) or group B (Calcitriol) for a period of 24 weeks. RESULTS:

Total 50 patients were enrolled in the study and were randomly assigned to I) Demographic Characteristics receive cinacalcet (28 patients) or Calcitriol (22 patients). The initial dose Mean age of the patients was 45.67 years for Cinacalcet treated group and of cinacalcet is 30 mg (once a day), Increased sequentially every four weeks 44.87 for Calcitriol treated group. Average weights of the patients were to 60, 90, 120 & 180 mg once daily and Clacitriol is 0.25 mcg daily, May be Comparable. The mean weight of patients was 55.25 kg & 57.29 respectively. increased by 0.25 mcg daily at intervals of 4-8 weeks. The dose was re- Out of 50 patients, 35 patients were males and the remaining 15 were duced if parathyroid hormone levels were less than 100 pg per milliliter females. A total of 50 patients were enrolled in the study. (10.6 pmol per liter) on three consecutive study visits or if patients re- ported an adverse event requiring. Dose adjustments were permitted at II) Drop–Outs and Managements four-week intervals during the efficacy assessment phase. There were two patients drop out from Calcitriol group. All 48 patients completed the study were included for statistical analysis. Patients were allowed to continue receiving vitamin-D sterols during this study if they were prescribed. Therefore, guidance was provided for changes III) Baseline Characteristics in the dose of vitamin-D. Patients were also permitted to continue to The mean body temperature was 98.05 °F for patients on Cinacalcet therapy receive phosphate-binding agents and participate in this study. Increases in & 98.160 F for patients on Calcitriol therapy at basal and 98.90 F and the dose of vitamin D sterols were permitted if parathyroid hormone levels 98.030 F temperature at the end of study in Cinacalcet and Calcitriol group rose by 50 percent or more from base line. respectively. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean body temperature Biochemical Determinations did not show any significant changes in both the groups. Plasma parathyroid hormone levels and serum calcium and phosphorus levels were measured at each study visit. Biochemical measurements were The mean pulse-rate was 81.05/min for patients of Cinacalcet therapy and made at central reference laboratory.

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 38-42 Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1),38-42 75.58/min for patients of Calcitriol therapy at basal. At the end of therapy Table 3 . Comparison in biochemical parameters between two groups pulse-rate was 82.00/min and 76.91/min for patients of Cinacalcet therapy Parameters Cinacalcet Calcitriol and Calcitriol therapy, respectively. There was no statistically significant difference between these groups (p>0.05). During and after the treatment, Mean PTH Level mean pulse-rate did not show any significant changes in both the groups. Base Line (pg/ml) 404.43 ± 224.39 495.09 ± 232.84 The average respiratory rate was 17.10/min for patients of Cinacalcet End of Therapy (pg/ml) 304.74 ± 327.27 387.99 ± 309.34 Percent Change 24.64% 21.63% therapy & 16.33/min for patients of Calcitriol therapy at basal. At the end Mean Serum Calcium Level of treatment, the respiratory rate was found to be18.94/min for patients of Base Line (mg/dl) 8.83 ± 0.47 8.76 ± 0.45 Cinacalcet therapy & 18.75/min for patients of Calcitriol therapy. There End of Therapy (mg/dl) 8.07 ± 0.96 8.72 ± 0.66 was no statistically significant difference between these groups (p>0.05). Percent Change 8.61% 0.46% During and after the treatment, mean respiratory rate did not show any Mean Serum Phosphorus Level significant changes in both the groups. Base Line (mg/dl) 4.65 ± 1.09 4.9 ± 1.41 End of Therapy (mg/dl) 5.70 ± 1.73 5.03 ± 1.26 Percent Change -22.58% -2.60% The average Blood Pressure of patients treated with Cinacalcet was 133.20/ Calcium-Phosphorus Ratio 82.90 mmHg and 129.45/78.00 mmHg of patients treated with Calcitriol at Base Line 29.48 ± 19.25 33.64 ± 17.33 basal & 134.73/84.89 mmHg of Cinacalcet group and131.09/83.27 mmHg End of Therapy 31.02±20.97 33.67± 19.25 of patients with Calcitriol treated group after the 24 week treatment. There Percent Change -5.22% -0.09% was no statistically significant difference between these groups (p>0.05). During and after the treatment, mean blood pressure did not show any p > 0.05 there was no statistical significant difference between the two groups.By significant changes in both the groups. z-test (between two groups)± values = mean ± SD Table 4. Global assessment of treatment by patients for efficacy IV) Efficacy Parameters Primary end point was achieved and following parameters were recorded Parameters Cinacalcet Calcitriol Excellent Efficacy a) PTH Levels: Number of Patients (%) 19 (67.86%) 06 (30.00%) Mean PTH level for patients treated with Cinacalcet tablet was signifi- Good Efficacy cantly decreased from 404.43 pg/ml to 304.74pg/ml (i.e. 24.64%) at the end Number of Patients (%) 08 (28.57%) 11 (55.00%) of treatment. In the same line there was significant decreased PTH level Poor Efficacy from 495.09 pg/ml to 387.99 pg/ml (i.e. 21.63%) for patients treated with Number of Patients (%) 01 (03.57%) 03 (15.00%) 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. p > 0.05 there was no statistical significant difference between the two groups.By Chi-Square test Table 1. Base-line demographic characteristics of patients Parameters Cinacalcet Calcitriol (Group-A) (Group-B) 600 Base Line End of Therapy No. of Patients 28 22 500 Age (yrs)* 45.67 ± 14.29 44.87±12.82 Weight (Kg)* 55.25±9.61 57.29±13.26 400 Sex Male 22 13 Female 6 9 300 p > 0.05 there was no statistical significant difference between the two groups.* By z-test (age & weight)± values = mean ± SD 200

Table 2. Comparison of patients examination between two groups PTH Level (pg/mL) 100 Parameters Cinacalcet Calcitriol Mean Body Temperature 0 Base Line (0F) 98.05 ± 0.77 98.16 ± 1.68 End of Therapy (0F) 98.9 ± 0.10 98.03 ± 1.3 Cinacalcet Calcitriol Mean Pulse Rate Base Line (per minute) 81.05 ± 8.78 82.00 ± 7.66 Figure 1: Comparison of PTH Level between Baseline and End of End of Therapy (per minute) 75.58 ± 9.49 76.91 ± 5.45 Therapy values Mean Respiratory Rate Base Line (per minute) 17.10 ± 1.33 18.94 ± 0.84 b) Serum Calcium Levels: End of Therapy (per minute) 16.33 ± 1.49 18.75 ± 0.86 Mean Serum calcium level for patients treated with Cinacalcet tablet was Mean Blood Pressure (Systolic) decreased from 8.83 mg/dL to 8.07 mg/dL (i.e. 8.61%) at the end of treat- Base Line (mm Hg) 133.20 ± 12.03 129.45 ± 02.31 ment. After the treatment with Calcitriol tablet decreased from 8.76 mg/dL End of Therapy (mm Hg) 134.73 ± 11.30 131.09 ± 09.29 to 8.72 mg/dL (i.e. 0.46%). There was no statistically difference (p>0.05) Mean Blood Pressure (Diastolic) in serum calcium level between the groups at the end of therapy. Base Line (mm Hg) 82.90 ± 10.92 78.00 ± 14.56 End of Therapy (mm Hg) 84.89 ± 0.95 83.27±6.92 c) Serum Phosphorus Levels: The mean serum phosphorus levels in patients treated with Cinacalcet was p > 0.05 there was no statistical significant difference between the two groups.By increased from 4.65mg/dL to 5.70mg/dL (i.e. 22.58%) at the end of therapy z-test (between two groups)± values = mean ± SD and after the treatment with Calcitriol from 4.9 mg/dL to 5.03 mg/dL (i.e. 2.6%).

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 38-42 Amol K Choulwar et al. / Journal of Pharmacy Research 2012,5(1),38-42 d) Calcium X Phosphorus Level: tion in young adults with end-stage renal disease who are undergoing The mean change in calcium x phosphorus level for patients treated with dialysis. N Engl J Med, 342, 2000, 1478-1483. Cinacalcet tablet was increased from 29.48 to 31.02 (i.e 5.22%) at the end 8. Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult of therapy. Similarly there was comparable increased in calcium x phospho- hemodialysis patients: a link between end-stage renal disease and rus level after the treatment wit Calcitriol tablet from 33.64 to 33.67 (i.e. cardiovascular disease? J Am Coll Cardiol, 39, 2002, 695-701. 0.09%). 9. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Asso- ciation of elevated serum PO4, Ca-PO4 product, and parathyroid V) Laboratory Investigations hormone with cardiac mortality risk in chronic hemodialysis pa- The comparison of laboratory parameters hemoglobin, CBC, SGOT, SGPT, tients. J Am Soc Nephrol, 12, 2001, 2131-2138. serum creatinine level, BUN, serum uric acid level, were done for both 10. Block GA, Port FK. Re-evaluation of risks associated with groups at basal & at the end of treatment. There were no statistically hyperphosphatemia and hyperparathyroidism in dialysis patients: difference (p>0.05) during and after the treatment, within the group. recommendations for a change in management. Am J Kidney Dis, 35, 2000, 1226-1237. 11. Johnson CA, McCarthy J, Bailie GR, Deane J, Smith S. Analysis of DISCUSSION: renal bone disease treatment in dialysis patients. Am J Kidney Dis, Our results indicate that cinacalcet effectively reduces parathyroid hor- 39, 2002, 1270-1277. mone levels in patients with secondary hyperparathyroidism who are re- 12. Indridason OS, Quarles LD. Comparison of treatments for mild sec- ceiving hemodialysis and ameliorates disturbances in serum calcium and ondary hyperparathyroidism in hemodialysis patients. Kidney Int, phosphorus that have been associated with adverse clinical outcomes. 57, 2000, 282-292. 13. Maung HM, Elangovan L, Frazao JM, et al. Efficacy and side effects The use of vitamin D sterols to lower parathyroid hormone levels, particu- of intermittent intravenous and oral doxercalciferol larly in combination with calcium-containing phosphate binders, can cause (1alphahydroxyvitaminD2) in dialysis patients with secondary hy- hypercalcemia and hyperphosphatemia by promoting intestinal absorp- perparathyroidism: a sequential comparison. Am J Kidney Dis, 37, tion of calcium and phosphorus.[24, 25, 26, 27] 2001, 532-543. 14. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization These disturbances often interrupt treatment, leading to inadequate bio- of an extracellular Ca2+ -sensing receptor from bovine parathyroid. chemical control and progression of bone disease. [26, 28] Such derangements Nature, 1993,366:575-580. are also associated with an increased risk of death, increased arterial stiff- 15. Nemeth EF, Steffey ME, Hammerland LG, et al. Calcimimetics with ness, and calcification of the coronary arteries, aorta, and cardiac valves.[8, 9, potent and selective activity on the parathyroid calcium receptor. 29-31] Proc Natl Acad Sci USA, 95,1998, 4040-4045. 16. Hammerland LG, Garrett JE, Hung BC, Levinthal C, Nemeth EF. 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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 38-42