Table of Contents
Overview:
Patients with chronic kidney disease usually have secondary hyperparathyroidism (SHPT), characterized by high levels of parathyroid hormone (PTH) circulation and a high risk of morbidity and mortality. Patients with SHPT are generally managed with a therapeutic combination that commonly involves calcimimetics. These calcimimetics and other agents, like vitamin D preparations, have recently become popular in clinical settings. Calcimimetics is a drug class that decreases PTH levels by targeting the calcium‐sensing receptor. Cinacalcet, a type of calcimimetic, is aggressively used; however, a high incidence of upper gastrointestinal (GI) tract‐related adverse events can lead to insufficient dosage and improper long‐term compliance. In 2018, Evocalcet was approved, which has equivalent efficacy to Cinacalcet with a lower clinical dose, improved bioavailability, reduced risk of upper gastrointestinal tract‐related adverse effects, and fewer safety concerns. This article focuses on Evocalcet and describes its clinical advantages in treating dialysis patients with SHPT.
For Patients:
What Is Hyperparathyroidism?
Before understanding the details about Evocalcet, it is essential to understand the underlying pathology of hyperparathyroidism. The parathyroid glands, located behind the thyroid gland, manage the calcium levels in the blood by secreting parathyroid hormone (PTH). In hyperparathyroidism, these glands produce excess PTH, increasing calcium levels in the blood (hypercalcemia). This dysregulation of calcium metabolism can result in many complications, like bone loss, cardiovascular issues, and impaired kidney function.
SHPT is a common complication in patients with chronic kidney disease (CKD) who undergo hemodialysis. As kidney function declines, there is a decreased capacity to excrete phosphorus, leading to hyperphosphatemia. This, in turn, stimulates the secretion of PTH, leading to SHPT. Left untreated, SHPT can contribute to the progression of CKD and increase the risk of cardiovascular events, fractures, and mortality. The management of SHPT has centered around using phosphate binders, vitamin D analogs, and calcimimetics. While these therapies can be helpful to some extent, they often come with limitations, including poor tolerability, dose-related adverse effects, and inadequate control of PTH levels. This underscores the need for innovative treatment options like Evocalcet.
Hyperparathyroidism poses a significant challenge to those afflicted with it. In the past, managing this condition has been a complex issue, generally requiring a combination of medications, dietary changes, and sometimes surgical intervention. However, the landscape of hyperparathyroidism treatment has been significantly regulated with the emergence of Evocalcet.
Evocalcet, a new calcimimetic agent, has garnered attention for its promising efficacy and safety profile in treating secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) undergoing hemodialysis. Evocalcet has rapidly become a cornerstone in managing hyperparathyroidism, offering patients and clinicians a new avenue for effective disease control.
What Are Calcimimetics?
Calcimimetics are compounds that resemble or potentiate the effects of extracellular Ca2+ on the CaR, leading to decreased secretion of parathyroid hormone (PTH) and inhibition of parathyroid gland cell proliferation. Early studies targeting the CaR for treating SHPT led to the discovery of NPS R‐568. This calcimimetic agent elevated the concentration of cytoplasmic Ca2+ and inhibited PTH secretion in the presence of extracellular Ca2+ in vitro. Though NPS R‐568 was developed as the first calcimimetic agent, its clinical development was suspended due to its undesirable pharmacokinetic properties, like extremely low bioavailability, and because it is primarily metabolized by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6. Next‐generation calcimimetic agents have evolved to overcome these issues.
Dosage:
The usual initial dosage for adults is one milligram (mg) of Evocalcet administered orally once daily. The starting dose can be two mg once daily, depending on the patient's condition. The subsequent oral dose is adjusted within the range of one to eight mg once daily while the patient's parathyroid hormone (PTH) and serum calcium levels are closely monitored. If the patient responds poorly, the dose can be increased to 12 mg once daily.
Why Is Evocalcet Prescribed?
Evocalcet is prescribed for the management of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) who are undergoing hemodialysis. SHPT is a common complication of CKD, particularly in patients receiving dialysis treatment, and is characterized by excessive secretion of parathyroid hormone (PTH) by the parathyroid glands.
The primary goal of treating SHPT with Evocalcet is to control elevated levels of PTH, calcium, and phosphorus in the blood, which are associated with adverse clinical outcomes such as bone mineral disorders, cardiovascular complications, and the progression of CKD. Evocalcet belongs to a class of medications known as calcimimetics. These medications work by mimicking the action of calcium on the calcium-sensing receptors (CaSR) in the parathyroid glands. By activating these receptors, Evocalcet helps to reduce the secretion of PTH, leading to improved regulation of calcium and phosphorus levels in the blood.
Storage:
Proper storage of medications like Evocalcet is essential to maintain stability and effectiveness.
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Temperature: To avoid exposure to extreme temperatures, it should be stored away from direct sunlight, heat sources, and moisture.
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Container: Evocalcet is often supplied in its original packaging, like a blister pack or a tightly closed container. Keeping the medication in its original packaging is important to protect it from light and moisture. Ensure the container is tightly closed when not in use to prevent air and moisture from entering.
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Accessibility: Keep Evocalcet out of reach of children and pets to prevent accidental ingestion. Store it securely, preferably in a locked cabinet or high shelf, to avoid unauthorized access.
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Expiry Date: Check the expiration date on the packaging of Evocalcet, and do not use it beyond this date. Expired medication may be less effective and may be potentially harmful. If the medication has expired, dispose of it correctly according to local regulations.
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Disposal: When disposing of unused or expired Evocalcet, do not flush it down the toilet or pour it down the drain unless specifically instructed. Instead, consult the pharmacist or local waste disposal facility for guidance on proper disposal methods, including medication take-back programs or community drug disposal initiatives.
By following these storage guidelines, the potency and safety of Evocalcet can be ensured for its intended therapeutic use. If an individual has questions or concerns about the storage of Evocalcet or any medication, consult the healthcare provider or pharmacist for assistance.
For Doctors:
Indications:
The primary reasons why Evocalcet may be prescribed include:
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Control of PTH Levels: Evocalcet helps lower elevated levels of PTH, a hallmark feature of SHPT. By reducing PTH secretion, Evocalcet helps to prevent complications associated with excessive PTH, such as bone loss and mineral metabolism abnormalities.
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Normalization of Calcium and Phosphorus Levels: Elevated calcium and phosphorus levels in the blood are expected in patients with SHPT. Evocalcet helps to bring these levels within the target range, thereby reducing the risk of complications such as vascular calcification and cardiovascular events.
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Reduction of Bone Disorders: SHPT can lead to bone mineral disorders, including osteoporosis and bone pain. By controlling PTH levels, Evocalcet may help mitigate these bone-related complications and improve bone health in patients with CKD.
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Cardiovascular Risk Reduction: Elevated levels of PTH, calcium, and phosphorus are related to an increased risk of cardiovascular events in patients with CKD. By regulating mineral metabolism parameters, Evocalcet may decrease the cardiovascular risk in this population.
Dosage and Administration:
The approved dosage of Evocalcet for the management of SHPT is up to 12 mg, which indicates that any decrease in intact PTH and, therefore, a higher guideline target success rate can be expected even in users if they were treated at higher dosages for more than 30 weeks. Another study of 52 weeks of treatment with Evocalcet up to 12 mg documented further improvement in serum PTH levels with no increase in safety concerns. More studies are required to confirm the long-term efficacy and safety of Evocalcet in natural clinical settings where patients might switch from Cinacalcet to Evocalcet.
Pharmacokinetics:
The pharmacokinetics of Evocalcet, like any medication, play an essential role in understanding how the drug is absorbed, distributed, metabolized, and excreted within the body. Here's an overview of the pharmacokinetic properties of Evocalcet:
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Absorption: Evocalcet is orally administered and rapidly absorbed from the gastrointestinal tract after ingestion. Its absolute bioavailability has been reported to be approximately 60 percent in healthy individuals. Food intake does not significantly affect its pharmacokinetics, allowing for flexibility in dosing with or without meals.
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Distribution: Evocalcet has a relatively high volume of distribution, indicating extensive tissue distribution beyond systemic circulation. It binds extensively to plasma proteins, primarily serum albumin. However, the extent of protein binding is not expected to be significantly affected by factors such as renal impairment.
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Metabolism: Metabolism is an essential aspect of Evocalcet's pharmacokinetic profile. The primary metabolic pathway involves hepatic metabolism mediated by cytochrome P450 (CYP) enzymes, particularly the CYP3A4 isoenzyme. Through this pathway, Evocalcet undergoes oxidation and conjugation to form inactive metabolites.
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Excretion: Evocalcet and its metabolites are predominantly eliminated through the hepatic route. Around 80 percent of the administered dose is excreted in feces, primarily as metabolites, while renal excretion accounts for a smaller proportion of elimination. The terminal half-life of Evocalcet is approximately 50 hours, indicating a prolonged duration of action and allowing for once-daily dosing.
Mechanism of Action of Evocalcet:
Evocalcet shows its therapeutic effects through its action as a calcimimetic agent. Calcimimetics resembles the effects of calcium on the parathyroid gland's calcium-sensing receptors (CaSR), thereby regulating PTH secretion. Evocalcet increases the receptors' sensitivity to extracellular calcium by binding to the CaSR, reducing PTH secretion. Unlike traditional calcimimetics like cinacalcet, Evocalcet offers several distinct advantages. Its excellent selectivity for the CaSR results in a more potent and sustained inhibition of PTH secretion, allowing for improved control of calcium and phosphorus levels. Further, Evocalcet has a longer half-life, enabling once-daily dosing and simplifying patient treatment regimens.
Chemical Taxonomy:
Description:
This compound belongs to the class of organic compounds known as phenyl pyrrolidine. These polycyclic aromatic compounds contain a benzene ring linked to a pyrrolidine ring through a CC or CN bond. Pyrrolidine is a five-membered saturated aliphatic heterocycle with one nitrogen atom and four carbon atoms.
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Kingdom - Organic compounds.
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Superclass - Organic heterocyclic compounds.
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Class - Pyrrolidines.
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Subclass - Phenyl pyrrolidine.
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Direct Parent - Phenyl pyrrolidine.
Clinical Efficacy and Safety Profile:
Several clinical trials have documented Evocalcet's efficacy in managing SHPT. In phase 3, a multicenter, randomized, double-blind study included hemodialysis patients with SHPT, Evocalcet effectively decreased PTH levels compared to placebo. Further, Evocalcet showed superiority over Cinacalcet in achieving and maintaining target PTH levels without compromising safety. Beyond its efficacy, Evocalcet has also exhibited a favorable safety profile. Common adverse effects associated with its use include vomiting, nausea, and diarrhea, which are generally mild to moderate in severity. Importantly, Evocalcet has shown a lower incidence of hypocalcemia than Cinacalcet, decreasing the need for dose adjustments and improving treatment adherence.
Precautions:
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Risk of Hypocalcemia: Evocalcet might decrease some patients' blood calcium levels (hypocalcemia). Be aware of the signs and symptoms of hypocalcemia, including numbness or tingling in the toes, fingers, or mouth, muscle cramps, and seizures. Contact the healthcare provider if any of these symptoms are experienced.
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Liver Function: Evocalcet is metabolized by the liver, so it may be necessary to monitor liver function in patients with pre-existing liver disease or impaired liver function. Inform the healthcare provider if there is any history of liver problems.
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Pregnancy and Breastfeeding: If one is pregnant or planning to get pregnant or breastfeeding, discuss the potential risks and benefits of taking Evocalcet with the healthcare provider. The safety of Evocalcet during pregnancy and breastfeeding has not yet been established, so use caution and follow the doctor's recommendations.
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Allergic Reactions: If a person has a known allergy to Evocalcet or its components, inform the healthcare provider before initiating treatment. Allergic reactions to Evocalcet are rare but can occur in some individuals.
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Dietary Considerations: Follow any dietary recommendations the healthcare provider or dietitian provides. Maintaining a balanced diet and avoiding foods high in calcium or phosphorus is essential, as these can affect the efficacy of Evocalcet and mineral metabolism.
Future Considerations:
The introduction of Evocalcet is considered an important advancement in the management of hyperparathyroidism, particularly in patients with chronic kidney disease (CKD) undergoing hemodialysis. It has a potent and selective action. Once-daily dosing and a favorable safety profile have made Evocalcet a promising therapeutic option for clinicians and patients.
Further research is needed to explore the long-term efficacy and safety of Evocalcet, specifically in real-world clinical settings. Efforts are being made to explain its potential role in other populations with hyperparathyroidism, like those with primary hyperparathyroidism or non-dialysis-dependent CKD. Evocalcet has led to a major shift in the treatment of hyperparathyroidism, providing a selective, potent, and well-tolerated treatment option for patients with SHPT. As the understanding of this innovative therapy continues to evolve, so will the ability to efficiently address the complex challenges of hyperparathyroidism in multiple patient populations.
