Cinacalcet on hemodialysis thrice weekly offers opportunities and challenges
Click Here to Manage Email Alerts
The medical management of mineral and bone disorders in people with end-stage kidney disease on dialysis is challenging for both patients and clinicians.
Many nephrologists approach the management of mineral and bone disorders in ESKD in a stepwise fashion, starting with dietary phosphorous restriction and an optimized dialysis prescription, followed by phosphate binders if hyperphosphatemia persists. If parathyroid hormone (PTH) levels are uncontrolled and hypercalcemia is absent, clinicians can begin active vitamin agents such as calcitriol.
In patients who continue to have severe elevations in PTH levels despite these interventions, calcimimetics are often utilized in an effort to avoid parathyroidectomy and preserve bone health. The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline update for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) recommends a target PTH of two to nine times the upper limit of normal for the PTH assay in use.1
Oral vs intravenous regimen
There are two calcimimetic drugs currently available in the United States. These include the oral agent Sensipar (cinacalcet, Amgen), which was approved by the FDA in 2004, and the intravenous drug Parsabiv (etelcalcetide, Amgen), which entered the market in 2017. Parsabiv is dosed three times per week at the end of dialysis due to its dialyzability.
Hypocalcemia is a complication of both agents but is seen more commonly with etelcalcetide and can contribute to QT interval prolongation and ventricular arrhythmias. Although both cinacalcet and etelcalcitide have been shown to be effective in lowering parathyroid hormone levels in head-to-head studies, cinacalcet dosed daily has been linked to high rates of medication non-adherence in clinical practice.2
In a 1-year study examining cinacalcet adherence in patients with ESKD on dialysis, the monthly refill rate declined from 58% in month 1 to 44% in month 12 (P = .055).3 This poor adherence was seen despite patients being enrolled in a state program that minimized copays to $2.50.
In addition, the medication possession ratio (MPR), defined as the sum of tablets supplied divided by the number of days between first and last fill, was greater than 80% in less than a third of patients in the 12-month period. MPR is a commonly used definition for good adherence.
In an analysis of nearly 5,000 patients on cinacalcet at a large dialysis organization, 45.6% of patients had not refilled their prescription for a period of 180 days or longer after 1 year.4 Of the remaining patients, about half had a MPR of greater than 80%. The gastrointestinal adverse events of cinacalcet may be one of the reasons that such poor adherence occurs, though similar rates of nausea and vomiting are also seen with etelcalcetide.5
Adherence issues
To address the adherence issues seen with cinacalcet, a number of groups have reported experiences with directly observed administration while a patient is on hemodialysis. These data are important not just from an adherence perspective, but also because the optimal frequency pattern of PTH suppression is unknown.
Pharmacokinetic studies of cinacalcet show PTH is maximally suppressed 2 to 3 hours after dosing but then rapidly returns to near pre-dose levels at 8 hours in patients on dialysis. In addition, the half-life of cinacalcet is 30 to 40 hours, suggesting it could potentially be dosed less frequently than once a day and remain effective.6
In a large, retrospective observational study of calcimimetic-naïve patients on hemodialysis who were initiated on three times weekly cinacalcet (n = 1,339) compared with patients started on daily cinacalcet (n = 6,871), intact PTH levels decreased in the follow-up period of 6 months for both groups.7 The fraction of patients achieving an iPTH of less than 600 mg/mL was similar in the two groups.
In addition, patients initiating three times weekly cinacalcet had higher levels of serum calcium and experienced fewer episodes of hypocalcemia than those on daily cinacalcet during the follow-up period, an important safety outcome.
In a study of 201 patients on hemodialysis who were transitioned from daily self-administration of cinacalcet to directly observed therapy at the end of hemodialysis three times a week, the mean intact parathyroid hormone (iPTH) level declined from 1,079 mg/mL at baseline to 987 mg/mL at 6 months.8
Calcium and phosphate levels were unchanged, and alkaline phosphatase declined from baseline to 6 months. Interestingly, the mean dose of cinacalcet declined from 130 mg/day at baseline to 87 mg/day at 6 months, potentially indicating that with better adherence with direct observed therapy less drug is necessary.
There are a number of other small reports detailing similar findings to the above larger investigations (see Table). At Satellite Healthcare, small pilot programs of protocolized cinacalcet three times per week conducted since January 2018 have demonstrated the operational feasibility of this approach. Parathyroid hormone control has been achievable and there have been no significant safety or adverse drug event reports.9
Summary
Mineral and bone disorders are typically managed using a step therapy approach with calcimimetics being utilized after other options have not adequately controlled iPTH. Cinacalcet and etelcalcitide can improve iPTH control, but cinacalcet dosed daily at home is linked to poor adherence rates and etelcalcitide is associated with higher rates of hypocalcemia.
Given the long half-life of cinacalcet, an option to address the poor adherence seen with cinacalcet daily is directly observed dosing three times per week on hemodialysis. A number of studies indicate this approach is safe and effective at controlling iPTH and making this option available to clinicians and patients is an important step forward in individualizing therapy.
- References:
- Kidney disease: Improving global outcomes (KDIGO) CKD-MBD update work group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention and treatment.
- Block GA, et al. JAMA.2017;doi:10.1001/jama.2016.19468.
- Gincherman Y, et al. Hemodial Int. 2010;doi:10.1111/j.1542-4758.2009.00397.x.
- Lee A, et al. J Med Econ.2011;doi:10.3111/13696998.2011.627404.
- Harris RZ, et al. Am J Kidney Dis. 2004;doi:10.1053/j.ajkd.2004.08.029.
- Sensipar (cinacalcet) package insert
- Sibbel S, et al. Comparison of 3 times weekly vs. daily administration of oral cinacalcet for the control of secondary hyperparathyroidism in patients receiving hemodialysis. Presented at National Kidney Foundation Spring Clinical Meetings (virtual), March 26-29, 2020.
- Demerdash TM, et al. Daily vs. post-dialysis administration of calcimimetics for the treatment of secondary hyperparathyroidism in hemodialysis patients: An interventional, multicenter study. Presented at American Society of Nephrology Kidney Week. Oct. 23-28, 2018; San Diego.
- Abra G, et al. Oral cinacalcet administered three times a week on hemodialysis: Clinical and operational feasibility. Satellite Healthcare medical director meeting. 2019. For more information:
- Graham Abra MD, is the senior director of medical clinical affairs at Satellite Healthcare and a clinical assistant professor at Stanford in the division of nephrology. He is also an associate editor on the Editorial Advisory Board for Nephrology News & Issues. He can be reached at abrag@satellitehealth.com.
- Rory Pace, MPH, RD, CSR, FAND, is the corporate director of nutrition services at Satellite Healthcare and can be reached at pacer@ satellitehealth.com.
- Tiffany Shang, PharmD, is a research pharmacologist within medical clinical affairs at Satellite Healthcare and can be reached at shangt@ satellitehealth.com.
Collapse
Read more about
Click Here to Manage Email Alerts