Etelcalcetide (Parsabiv®): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Etelcalcetide, marketed under the brand name Parsabiv®, is a second-generation, intravenous calcimimetic agent developed for the management of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) undergoing hemodialysis. As a synthetic oligopeptide, its primary mechanism of action is the agonism of the calcium-sensing receptor (CaSR) on the parathyroid gland, which suppresses the synthesis and secretion of parathyroid hormone (PTH). This action leads to subsequent reductions in serum calcium and phosphorus levels, addressing the core biochemical derangements of SHPT.

Clinical development has established Etelcalcetide's superior efficacy in reducing PTH levels compared to both placebo and the first-generation oral calcimimetic, cinacalcet. Pivotal Phase III trials demonstrated that a significantly greater proportion of patients treated with Etelcalcetide achieved clinically meaningful reductions in PTH. A key advantage of Etelcalcetide is its intravenous route of administration, which is performed by healthcare professionals at the end of each hemodialysis session. This approach guarantees 100% bioavailability and completely bypasses the significant patient adherence challenges associated with daily oral therapies like cinacalcet, a factor that amplifies its efficacy in real-world clinical practice.

The primary safety consideration for Etelcalcetide is its potent calcium-lowering effect, which can lead to hypocalcemia. This on-target effect necessitates a rigorous risk management protocol, including contraindication in patients with low baseline calcium and a strict schedule for monitoring serum calcium and PTH levels, particularly upon initiation and after any dose adjustment.

Etelcalcetide represents a significant therapeutic advancement for a complex and vulnerable patient population. Ongoing research is focused on elucidating its long-term effects on critical clinical outcomes, such as cardiovascular events and bone health, as suggested by promising data on its ability to favorably modulate markers like Fibroblast Growth Factor 23 (FGF23) and inhibit the progression of left ventricular hypertrophy.

Drug Identification and Physicochemical Properties

Nomenclature and Identifiers

Etelcalcetide is identified by a variety of names and codes across clinical, research, and regulatory domains, ensuring its unambiguous recognition.

• Generic Name: Etelcalcetide (International Nonproprietary Name [INN] and United States Adopted Name).[1]
• Proprietary Name: Parsabiv®.[1]
• Developmental and Code Names: AMG 416, KAI-4169, ONO-5163.[1]
• Alternative Names: The compound has also been referred to as Velcalcetide and Telcalcetide.[1]
• Chemical Identifiers:
• CAS Number: 1262780-97-1 (free base); 1334237-71-6 (hydrochloride salt).[4]
• DrugBank ID: DB12865.[2]
• UNII (Unique Ingredient Identifier): 60ME133FJB.[1]
• InChI Key: ANIAZGVDEUQPRI-ZJQCGQFWSA-N.[2]

Chemical Structure and Composition

The molecular architecture of Etelcalcetide is a key determinant of its pharmacological profile, featuring several unique structural elements designed for stability and targeted action.

• Molecular Formula: C38​H73​N21​O10​S2​.[1]
• Molecular Weight: The molecular weight of the free base is approximately 1048.26 g/mol.[1]
• Structural Description: Etelcalcetide is a synthetic oligopeptide, consisting of a sequence of eight amino acids.[1] Its precise chemical structure is defined as N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide, which forms a disulfide bond with a molecule of L-cysteine.[1] The full IUPAC name is N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide (1->1')-disulfide compound with L-cysteine.[1]
• Key Structural Features: A defining characteristic of Etelcalcetide is its peptide backbone, which is composed predominantly of D-amino acids rather than the naturally occurring L-amino acids.[3] This unnatural stereochemistry is a deliberate and critical design feature. This structure confers significant resistance to degradation by endogenous proteases, which are stereospecific and primarily recognize L-amino acid configurations. This inherent stability against enzymatic breakdown is a direct contributor to the drug's prolonged duration of action and its long effective half-life of 3 to 5 days in hemodialysis patients, making it suitable for intermittent, thrice-weekly dosing that aligns perfectly with the typical hemodialysis schedule.[3]

Furthermore, the disulfide bond with L-cysteine is not merely a static linker but a dynamic component that governs the drug's distribution and clearance. Pharmacokinetic studies reveal that Etelcalcetide undergoes a reversible disulfide exchange with endogenous thiols in the bloodstream, leading to the formation of covalent conjugates, predominantly with serum albumin.[2] Serum albumin, a large protein with a molecular weight of approximately 67 kDa, is too large to be cleared by the hemodialysis membrane.[13] This covalent binding effectively creates a large, circulating reservoir of the drug that is protected from removal during dialysis. Because the binding is reversible, Etelcalcetide is gradually released from its albumin-bound state back into the plasma, particularly after a dialysis session has cleared the free drug. This process partially restores plasma concentrations and functions as an intrinsic sustained-release mechanism, ensuring a continuous therapeutic effect in the days between dialysis sessions and explaining its long effective half-life.[13]

Drug Classification

Etelcalcetide is categorized under several classification systems that reflect its chemical nature, mechanism, and therapeutic application.

• Modality: Small Molecule.[2]
• Pharmacological Class: Calcimimetic; Calcium-Sensing Receptor (CaSR) Agonist.[1]
• Therapeutic Class: Anti-Parathyroid Agent.[1]
• Anatomical Therapeutic Chemical (ATC) Classification: H05BX04 (Other anti-parathyroid agents), under the broader categories of H05B (Anti-Parathyroid Agents) and H05 (Calcium Homeostasis).[1]

Pharmacology

Mechanism of Action (Pharmacodynamics)

Etelcalcetide exerts its therapeutic effects through direct and potent modulation of the calcium-sensing receptor, a key regulator of mineral homeostasis.

• Molecular Target: The primary molecular target of Etelcalcetide is the extracellular calcium-sensing receptor (CaSR), a Class C G-protein coupled receptor located on the surface of various cells, most importantly the chief cells of the parathyroid gland.[2]
• Mode of Action: As a calcimimetic agent, Etelcalcetide mimics the physiological action of extracellular calcium on the CaSR.[3] It functions as an allosteric modulator and a direct agonist. It binds to the CaSR and enhances the receptor's sensitivity and activation by ambient extracellular calcium.[2] Some evidence further suggests that it can act as a direct agonist, capable of inducing a slight activation of the CaSR even in the absence of calcium.[22]
• Molecular Interaction: The interaction between Etelcalcetide and the CaSR is highly specific. Research has established the critical importance of a disulfide bond formed between a cysteine residue within the Etelcalcetide peptide and the Cys482 residue located in the extracellular domain of the human CaSR. Experimental studies have demonstrated that mutating this Cys482 residue to serine or tyrosine in the human CaSR completely ablates the activity of Etelcalcetide. Conversely, introducing a cysteine at this position in the pig CaSR, which naturally has a tyrosine and is unresponsive to the drug, confers full activity. This provides strong evidence for a specific, covalent interaction that is essential for the drug's pharmacological action.[6]
• Cellular and Physiological Effect: The activation of the CaSR on parathyroid chief cells triggers intracellular signaling cascades that inhibit the synthesis and secretion of PTH.[2] This effect is rapid and dose-dependent; following a single intravenous bolus dose, PTH levels begin to decrease within 30 minutes.[2] The sustained reduction in circulating PTH levels leads to the desired downstream physiological consequences: decreased mobilization of calcium from bone and altered renal handling of minerals. This results in a reduction in both serum calcium and serum phosphorus concentrations, thereby addressing the hallmark biochemical abnormalities of SHPT.[2]

Pharmacokinetics (ADME)

The pharmacokinetic profile of Etelcalcetide is uniquely adapted to its target patient population, characterized by intravenous administration, a distinct metabolic pathway, and clearance dependent on hemodialysis.

• Absorption: Etelcalcetide is administered exclusively via the intravenous route, resulting in 100% bioavailability.[14]
• Distribution: The drug exhibits a large apparent volume of distribution (Vd​) of approximately 796 L, indicating extensive distribution into tissues.[8] As previously described, it is predominantly bound to plasma albumin through a reversible covalent disulfide bond, while non-covalent binding to plasma proteins is low.[2] The ratio of Etelcalcetide concentration in whole blood to plasma is approximately 0.6.[2]
• Metabolism: Etelcalcetide's metabolic profile confers a significant clinical advantage. It is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450) enzymes.[2] This is a crucial feature, as many common drug-drug interactions (DDIs) are mediated through the CYP450 system. The CKD-hemodialysis population is characterized by extensive polypharmacy, which elevates the risk of such interactions. The metabolic inertness of Etelcalcetide with respect to this system means it is highly unlikely to be involved in common metabolic DDIs, simplifying its integration into complex medication regimens and reducing the risk of unexpected toxicity or therapeutic failure. Instead of hepatic metabolism, its primary transformation pathway is biotransformation in the blood via reversible disulfide exchange with endogenous thiols, leading to the formation of conjugates, mainly with serum albumin.[2] Plasma exposure to these biotransformation products is approximately five times higher than that of the parent drug.[2]
• Elimination: The elimination of Etelcalcetide is highly dependent on renal function. In individuals with normal kidney function, it is cleared via renal excretion.[13] However, in its indicated population of patients with end-stage renal disease, hemodialysis becomes the predominant route of elimination.[13] Clinical studies have shown that approximately 60% of an administered dose is recovered in the dialysate during a hemodialysis session.[13] The drug exhibits triexponential decay, and its effective terminal half-life in patients undergoing hemodialysis three times a week is long, estimated at 3 to 5 days.[3] The systemic clearance is estimated to be 7.66 L/hr.[2]

Table 1: Key Physicochemical and Pharmacokinetic Properties of Etelcalcetide

Parameter	Value / Description	Source(s)
DrugBank ID	DB12865	2
CAS Number	1262780-97-1 (free base)	2
Molecular Formula	C38​H73​N21​O10​S2​	1
Molecular Weight	1048.26 g/mol (free base)	5
Drug Class	Calcimimetic, CaSR Agonist, Anti-Parathyroid Agent	2
Mechanism of Action	Allosteric modulator and agonist of the Calcium-Sensing Receptor (CaSR), suppressing PTH secretion.	3
Bioavailability	100% (Intravenous administration)	14
Volume of Distribution (Vd​)	~796 L	8
Plasma Protein Binding	Predominantly bound to albumin via reversible covalent disulfide bond.	2
Metabolism Pathway	Not metabolized by CYP450 enzymes. Biotransformed in blood by reversible disulfide exchange.	2
Primary Elimination Route	Hemodialysis in patients with end-stage renal disease.	13
Effective Half-Life	3 to 5 days (in hemodialysis patients)	8
Clearance	7.66 L/hr	2

Clinical Efficacy and Pivotal Trials

Indication and Therapeutic Goal

Etelcalcetide has a specific and well-defined therapeutic role in the management of CKD-Mineral and Bone Disorder (CKD-MBD).

• Approved Indication: Etelcalcetide is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.[1]
• Therapeutic Goal: The primary objective of therapy is to reduce pathologically elevated PTH levels to a target range (e.g., a predialysis PTH level of ≤300 pg/mL was a key secondary endpoint in pivotal trials) and to normalize associated mineral imbalances, such as hypercalcemia and hyperphosphatemia.[8]
• Limitations of Use: The use of Etelcalcetide has not been studied and is therefore not recommended in patients with parathyroid carcinoma, primary hyperparathyroidism, or in patients with CKD who are not on hemodialysis.[8]

Phase I and II Clinical Trials

Early-phase clinical trials were instrumental in establishing the foundational safety, pharmacokinetic profile, and proof-of-concept for Etelcalcetide. Phase I studies in both healthy male volunteers and hemodialysis patients confirmed its tolerability and dose-proportional pharmacokinetics.[27] Subsequent Phase II trials provided robust evidence of its efficacy. One study demonstrated that Etelcalcetide achieved a mean PTH reduction of 49%, in stark contrast to a 29% increase observed in the placebo group.[3] Another Phase II trial found that 89% of patients treated with Etelcalcetide experienced a reduction in PTH of 30% or more.[3] These unequivocally positive results validated the therapeutic potential of the molecule, leading to its acquisition by Amgen from KAI Pharmaceuticals and its advancement into a large-scale Phase III development program.[3]

Phase III Placebo-Controlled Trials

The cornerstone of Etelcalcetide's regulatory approval was a pair of large, 26-week, randomized, double-blind, placebo-controlled Phase III trials. These studies, involving a combined total of 1,023 patients with moderate-to-severe SHPT on hemodialysis, were designed to definitively establish its efficacy and safety.[8]

• Primary Endpoint: The primary efficacy measure in both trials was the proportion of patients achieving a greater than 30% reduction in mean PTH from baseline during the efficacy assessment phase (defined as weeks 20 through 27).
• Key Results: The results were overwhelmingly positive and demonstrated the profound superiority of Etelcalcetide over placebo. Across the two studies, 74% to 77% of patients in the Etelcalcetide arms achieved the primary endpoint, compared with only 8% to 11% of patients in the placebo arms (P <.001).[8]
• Secondary Endpoints: Etelcalcetide also demonstrated statistically significant superiority in all key secondary endpoints. A much larger proportion of patients treated with Etelcalcetide achieved a mean PTH level of 300 pg/mL or lower (52% to 56%) compared to those receiving placebo (5% to 6%). Furthermore, treatment led to significant reductions from baseline in serum calcium and phosphorus levels.[8]

Long-Term Efficacy and Safety (Open-Label Extension Studies)

To evaluate the durability of its effects and its long-term safety profile, eligible patients from the pivotal trials were enrolled in a 52-week, single-arm, open-label extension (OLE) study (NCT01785875). This study included 891 patients and provided crucial data on extended treatment.[11]

• Sustained Efficacy: The OLE study confirmed that the potent PTH-lowering effect of Etelcalcetide is sustained over at least one year of continuous treatment. Approximately 68% of patients maintained a greater than 30% reduction in PTH from baseline, and 56% achieved a PTH level of 300 pg/mL or less. The average dose of Etelcalcetide remained relatively stable throughout the study, suggesting an absence of tachyphylaxis or loss of effect over time.[11]
• Long-Term Safety: Importantly, no new safety signals were identified during the 52-week extension. The incidence, nature, and severity of adverse events, with hypocalcemia being the most prominent, were consistent with those observed in the shorter-term, placebo-controlled trials, indicating a predictable and manageable long-term safety profile.[11]

Emerging Research on Surrogate and Clinical Outcomes

While the primary approval for Etelcalcetide was based on its ability to control biochemical markers, ongoing research is exploring its potential impact on hard clinical outcomes, particularly cardiovascular and bone health. SHPT is a systemic disorder, and its treatment value may extend beyond PTH control. Elevated levels of Fibroblast Growth Factor 23 (FGF23), for example, are a key pathogenic factor in CKD-MBD and are strongly associated with left ventricular hypertrophy (LVH) and adverse cardiovascular outcomes.[14]

• Cardiac Hypertrophy: The ETECAR-HD randomized controlled trial provided compelling evidence in this area. It compared Etelcalcetide with the active vitamin D analog alfacalcidol in hemodialysis patients with established LVH. Over 12 months, treatment with Etelcalcetide was shown to inhibit the progression of LVH, an effect that was strongly correlated with its ability to significantly decrease FGF23 levels. In contrast, alfacalcidol treatment was associated with an increase in FGF23.[5] This suggests that Etelcalcetide's mechanism provides a dual benefit: it directly treats hyperparathyroidism by lowering PTH while also favorably modulating a critical cardiovascular risk factor (FGF23). This positions it as a potentially disease-modifying agent for the cardiovascular complications of CKD-MBD.
• Bone and Vascular Health: The long-term effects on bone architecture and vascular calcification are under active investigation. The ongoing trial NCT03960437 is designed to directly assess the effects of a 9-month treatment course with Etelcalcetide on bone strength (measured by bone biopsy) and the serum propensity to cause vascular calcification.[33] Additionally, the ETERNITY-ITA study is evaluating its effect on vitamin K-dependent proteins involved in bone and vascular health.[34]
• Pediatric Studies: Recognizing the need for effective treatments in younger populations, the development program has been extended to pediatric patients. A Phase 3 study (NCT03633708) is currently recruiting children and adolescents (ages 2 to 18) with SHPT on hemodialysis to evaluate the efficacy, safety, and pharmacokinetics of Etelcalcetide in this population, with an estimated completion date between 2025 and 2029.[34]

Table 2: Summary of Pivotal Phase III Clinical Trial Efficacy Endpoints

Endpoint	Etelcalcetide Arm (%)	Comparator Arm (%)	P-value	Source(s)
Placebo-Controlled Trials (Pooled Data)
>30% PTH Reduction (Primary Endpoint)	74.7	8.9 (Placebo)	<.001	8
>50% PTH Reduction	-	-	-
Proportion with PTH ≤300 pg/mL	54.0 (average)	5.5 (average)	<.001	8
Active-Comparator Trial (vs. Cinacalcet)
>30% PTH Reduction (Primary Endpoint)	68.2	57.7 (Cinacalcet)	<.001 (non-inferiority) .004 (superiority)	8
>50% PTH Reduction	52.4	40.2 (Cinacalcet)	.001	8
Proportion with PTH ≤300 pg/mL	-	-	-

Comparative Analysis: Etelcalcetide vs. Cinacalcet

Cinacalcet, the first-generation oral calcimimetic, serves as the primary clinical comparator for Etelcalcetide. A detailed comparison highlights key differences in pharmacology, administration, efficacy, and real-world effectiveness.

Pharmacological and Administrative Distinctions

• Administration and Adherence: The most significant practical difference is the route of administration. Etelcalcetide is given intravenously three times weekly by a healthcare professional at the end of a hemodialysis session, ensuring 100% adherence.[3] Cinacalcet is a daily oral medication, which is subject to patient non-adherence, a well-documented problem in the dialysis population due to high pill burden and gastrointestinal side effects.[14]
• Mechanism and Potency: While both are calcimimetics, subtle mechanistic differences exist. Cinacalcet is classified as an allosteric modulator of the CaSR, whereas Etelcalcetide is described as a direct CaSR agonist.[22] Clinical and preclinical data suggest that Etelcalcetide is a more potent agent for reducing PTH levels.[22]

Head-to-Head Clinical Trial Efficacy

A pivotal 26-week, randomized, double-blind, double-dummy trial directly compared the efficacy and safety of IV Etelcalcetide with oral cinacalcet in 683 hemodialysis patients.[8]

• Primary Endpoint: The trial was designed to demonstrate the non-inferiority of Etelcalcetide to cinacalcet. It successfully met this endpoint, with 68.2% of patients on Etelcalcetide achieving a >30% reduction in PTH compared to 57.7% on cinacalcet.[8]
• Superiority on Secondary Endpoints: Etelcalcetide went on to demonstrate statistical superiority over cinacalcet on the same endpoint (p=0.004) and on the more stringent secondary endpoint of achieving a >50% reduction in PTH (52.4% vs. 40.2%, p=0.001).[8]

Safety and Tolerability Profile Comparison

The safety profiles of the two drugs are broadly similar, driven by their shared mechanism of action, but with some notable differences.

• Hypocalcemia: Etelcalcetide's greater potency translates to a higher incidence of hypocalcemia. In the head-to-head trial, decreased blood calcium was reported in 68.9% of Etelcalcetide patients versus 59.8% of cinacalcet patients.[12] Etelcalcetide appears to lower serum calcium more substantially than cinacalcet.[22]
• Gastrointestinal Intolerance: Both drugs are known to cause GI side effects. However, in the direct comparison trial, rates of nausea (18.3% for Etelcalcetide vs. 22.6% for cinacalcet) and vomiting (13.3% vs. 13.8%) were comparable or slightly lower with Etelcalcetide, suggesting it may be better tolerated from a GI perspective.[14]
• Cardiac Events: The head-to-head trial reported a higher incidence of treatment-emergent events related to cardiac failure in the Etelcalcetide arm (3.0%) compared to the cinacalcet arm (0.6%).[38] However, a larger integrated safety analysis pooling data from five pivotal trials concluded that the overall safety profiles of the two drugs were comparable.[42]

Real-World Effectiveness and Adherence

The distinction between efficacy in a controlled trial and effectiveness in routine clinical practice is critical. The IV administration of Etelcalcetide provides an "adherence advantage" that appears to amplify its efficacy superiority in the real world. Observational studies comparing outcomes in US dialysis facilities that preferentially use Etelcalcetide versus those that primarily use cinacalcet have shown a much larger performance gap than was seen in the randomized trial.[41] Facilities that switched their primary calcimimetic from cinacalcet to Etelcalcetide saw their patients' mean PTH levels decrease dramatically (e.g., from 671 pg/mL to 484 pg/mL). In contrast, facilities that continued to primarily use cinacalcet saw patient PTH levels increase over the same period. This suggests that the guaranteed drug delivery of Etelcalcetide overcomes the adherence barriers of oral cinacalcet, leading to substantially better biochemical control in a real-world setting.[41]

Cost-Effectiveness Analysis

The economic value of Etelcalcetide relative to cinacalcet has been a subject of debate. A life-time Markov model developed from a European perspective suggested that Etelcalcetide could be cost-effective, with incremental cost-effectiveness ratios (ICERs) ranging from €1,355 to €47,687 per quality-adjusted life year (QALY) gained, depending on pricing assumptions.[45] However, health technology assessment bodies like the UK's National Institute for Health and Care Excellence (NICE) have expressed significant uncertainty. While acknowledging Etelcalcetide's clinical superiority on biochemical endpoints, NICE questioned the strength of the evidence linking these surrogate marker improvements to long-term reductions in hard clinical outcomes like mortality and fractures. This uncertainty led to a more restrictive recommendation, positioning Etelcalcetide as an option primarily for patients for whom cinacalcet is unsuitable.[46]

Table 3: Comparative Profile of Etelcalcetide and Cinacalcet

Feature	Etelcalcetide	Cinacalcet	Source(s)
Administration Route	Intravenous (IV)	Oral	22
Dosing Frequency	Three times weekly (with dialysis)	Daily	14
Mechanism	Direct CaSR Agonist	Allosteric CaSR Modulator	22
Potency	Higher	Lower	22
Efficacy (>50% PTH reduction)	52.4%	40.2%	8
Incidence of Hypocalcemia	Higher (68.9% reported decreased Ca)	Lower (59.8% reported decreased Ca)	12
Incidence of Nausea	18.3%	22.6%	38
Adherence Consideration	Guaranteed (provider-administered)	Variable (patient-dependent)	39

Safety, Tolerability, and Risk Management

The safety profile of Etelcalcetide is well-characterized and is dominated by on-target effects related to its potent activation of the CaSR.

Adverse Event Profile

• Common Adverse Events: The most frequently reported adverse events, occurring in more than 10% of patients in clinical trials, are direct pharmacological consequences of PTH suppression and calcium reduction. These include decreased blood calcium (hypocalcemia), muscle spasms, diarrhea, nausea, and vomiting.[3] Headache is also commonly reported.[15]
• Serious Adverse Events: While less common, serious adverse events can occur, primarily as a result of severe hypocalcemia. These include seizures, prolongation of the QT interval on an electrocardiogram, and subsequent ventricular arrhythmias.[14] Additionally, cases of worsening heart failure, hypotension, and decreased myocardial performance have been reported in clinical trials.[14] Rare instances of upper gastrointestinal bleeding have been observed, though a definitive causal relationship with the drug has not been established.[14]

Key Warnings and Precautions

The prescribing information for Etelcalcetide includes several important warnings to mitigate potential risks.

• Hypocalcemia: This is the most significant safety concern and the primary dose-limiting toxicity. The drug's potent calcium-lowering effect is an extension of its therapeutic action, but excessive reduction poses serious risks. Therefore, the management of Etelcalcetide therapy is fundamentally about managing its induced hypocalcemia. It is contraindicated for initiation in patients with a corrected serum calcium level below the lower limit of the normal range.[3]
• Heart Failure: Cases of worsening congestive heart failure have been reported. Patients, particularly those with a pre-existing history of heart failure, should be monitored closely for worsening signs and symptoms.[14]
• Adynamic Bone Disease: Chronic and excessive suppression of PTH levels (e.g., consistently below 100 pg/mL) can disrupt normal bone remodeling, leading to adynamic bone disease, a condition characterized by low bone turnover and increased fracture risk. If PTH levels fall below the target range, the dose of Etelcalcetide should be reduced or the drug temporarily discontinued.[3]
• Seizure Disorder: Because significant reductions in serum calcium can lower the seizure threshold, Etelcalcetide should be used with caution in patients with a known history of a seizure disorder.[14]

Contraindications and Drug Interactions

• Contraindications: Etelcalcetide is contraindicated in patients with known hypersensitivity to the drug or any of its excipients and in patients with hypocalcemia at the time of initiation.[3]
• Drug-Drug Interactions: The most critical interaction is with other calcimimetics. Co-administration of Etelcalcetide and cinacalcet is contraindicated due to the additive effects on the CaSR, which can result in severe, life-threatening hypocalcemia. When transitioning a patient from cinacalcet to Etelcalcetide, cinacalcet must be discontinued for at least 7 days before the first dose of Etelcalcetide is administered.[16] Caution is also advised when co-administering Etelcalcetide with any other medications known to lower serum calcium.[48]

Risk Management and Monitoring Protocol

Safe use of Etelcalcetide is contingent upon strict adherence to a predefined monitoring protocol.

• Serum Calcium Monitoring: Corrected serum calcium must be measured prior to initiating therapy, within one week after initiation or any dose adjustment, and then every four weeks during maintenance therapy.[26]
• PTH Level Monitoring: Intact PTH levels should be measured four weeks after initiation or any dose adjustment to assess the therapeutic response. Once a stable maintenance dose is established, PTH should be monitored according to routine clinical practice.[47]
• Patient Education: Patients must be thoroughly educated on the signs and symptoms of hypocalcemia (e.g., paresthesias, myalgias, muscle spasms, numbness or tingling around the mouth) and instructed to report them to their healthcare provider immediately.[24]

Dosage, Administration, and Practical Considerations

The practical application of Etelcalcetide therapy requires careful attention to dosing, administration technique, and storage to ensure both safety and efficacy.

Dosing and Titration

The dosing of Etelcalcetide is individualized through a careful titration process guided by laboratory monitoring.

• Initial Dose: The recommended starting dose for all patients is 5 mg, administered as an intravenous (IV) bolus three times per week at the conclusion of hemodialysis.[47]
• Titration: The dose should be adjusted based on the patient's PTH and corrected serum calcium levels. Dose increases may be made in increments of 2.5 mg or 5 mg, but no more frequently than every four weeks. The maximum approved dose is 15 mg three times per week.[47]
• Maintenance Dose: The goal of titration is to establish the lowest effective maintenance dose that keeps PTH within the target range while maintaining normocalcemia. The typical maintenance dose ranges from 2.5 mg to 15 mg three times per week. The average dose used during the efficacy assessment phase of clinical trials was 7.2 mg.[47]
• Dose Reduction or Interruption: The dose must be reduced or therapy temporarily discontinued if PTH levels are suppressed below the target range or if hypocalcemia develops. Specific protocols guide the re-initiation of therapy at a lower dose once calcium levels have been restored.[50]

Administration Protocol

Proper administration technique is crucial to prevent drug loss and ensure the full dose is delivered.

• Timing: The drug must be administered at the end of the hemodialysis treatment. This is a critical step because Etelcalcetide is a small molecule that is effectively removed by the dialyzer membrane. Administration must occur after blood is no longer circulating through the dialyzer to avoid premature clearance of the dose.[47]
• Method: Etelcalcetide is given as an IV bolus injection into the venous line of the dialysis circuit. This can be done either during the saline rinse-back process or intravenously after rinse-back is complete.[47]
• Flushing: To ensure the entire dose is washed out of the dialysis tubing and into the patient's systemic circulation, the line must be flushed with a sufficient volume of saline. A flush of at least 150 mL of saline is recommended if given during rinse-back, or at least 10 mL of saline if given after rinse-back.[47]
• Preparation: Etelcalcetide is supplied as a clear, colorless solution in single-dose vials of 2.5 mg, 5 mg, and 10 mg strengths. It should be visually inspected for particulate matter and discoloration before use and should not be mixed or diluted.[49]

Management of Special Scenarios

• Missed Doses: If a patient misses a regularly scheduled hemodialysis treatment, the corresponding dose of Etelcalcetide should be skipped. Therapy should resume at the prescribed dose at the end of the next hemodialysis session. If a patient misses more than two weeks of hemodialysis treatments, Etelcalcetide should be reinitiated at the recommended starting dose of 5 mg (or 2.5 mg if that was the patient's last dose) to mitigate the risk of hypocalcemia.[47]
• Switching from Cinacalcet: As noted, a washout period of at least 7 days after the last dose of cinacalcet is mandatory before initiating Etelcalcetide to prevent severe hypocalcemia from overlapping pharmacodynamic effects.[17]

Storage and Handling

• Refrigeration: Vials of Etelcalcetide must be stored under refrigeration at 2°C to 8°C (36°F to 46°F). They must be kept in the original carton to protect the drug from light.[47]
• Room Temperature Stability: Once a vial is removed from the refrigerator, it can be stored in its original carton for up to 7 days, provided it is not exposed to temperatures above 25°C (77°F). If removed from the carton, it is exposed to light and must be used within 4 hours.[47]

Table 4: Dosing and Monitoring Schedule for Etelcalcetide

Phase of Treatment	Action / Dose	Monitoring Parameter	Monitoring Frequency
Initiation	Ensure baseline corrected serum calcium is at or above lower limit of normal. Start with 5 mg IV TIW at end of dialysis.	Corrected Serum Calcium Intact PTH	Within 1 week of initiation. At 4 weeks after initiation.
Titration	If PTH is above target and calcium is normal, increase dose in 2.5 mg or 5 mg increments. Maximum dose: 15 mg TIW.	Corrected Serum Calcium Intact PTH	Within 1 week of dose adjustment. At 4 weeks after dose adjustment.
Maintenance	Continue individualized dose (2.5 mg to 15 mg TIW) that maintains target PTH and normal calcium.	Corrected Serum Calcium Intact PTH	Every 4 weeks. Per clinical practice.
Hypocalcemia Management	If calcium falls below 7.5 mg/dL or symptoms occur, STOP therapy and treat hypocalcemia. Reinitiate at a dose 5 mg lower than the last dose once calcium is normal and symptoms resolve.	Corrected Serum Calcium	As clinically indicated.
PTH Over-suppression	If PTH falls below target range, reduce dose or temporarily discontinue therapy.	Intact PTH	As clinically indicated.

Regulatory and Developmental History

The journey of Etelcalcetide from a developmental compound to a globally approved therapy involved key strategic acquisitions and a robust clinical trial program.

Timeline of Development

Etelcalcetide was originally discovered and developed by KAI Pharmaceuticals under the code name KAI-4169.[3] Following the successful completion of Phase II trials that demonstrated its potent PTH-lowering effects, the company and its asset became a high-value target. In 2012, Amgen acquired KAI Pharmaceuticals for $315 million, taking over the late-stage development of the compound, which was renamed AMG 416.[3] In parallel, KAI had entered into an agreement with Ono Pharmaceutical in 2011 for the co-development and commercialization of the drug in Japan.[3]

U.S. Food and Drug Administration (FDA) Approval

Amgen advanced the compound through a comprehensive Phase III program and submitted a New Drug Application (NDA) to the FDA in August 2015.[3] The FDA granted its approval for Parsabiv® (etelcalcetide) on February 7, 2017.[2] The approval was a notable event in nephrology, as Etelcalcetide was the first new therapeutic agent approved for the treatment of SHPT in over a decade, offering a novel mechanism and route of administration for this challenging condition.[39]

European Medicines Agency (EMA) Approval

The regulatory process in Europe proceeded on a similar timeline. Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), the European Commission granted a centralized marketing authorization for Parsabiv® on November 11, 2016.[1] The approval, which applies to all member states of the European Union, was based on the strength of the data from the three pivotal Phase III studies: the two placebo-controlled trials and the head-to-head active-comparator trial against cinacalcet.[29]

Conclusion and Future Directions

Synthesis of Clinical Profile

Etelcalcetide is a highly potent, second-generation calcimimetic that has established itself as a significant therapeutic option for the management of secondary hyperparathyroidism in the hemodialysis population. Its clinical profile is defined by a combination of superior efficacy and a unique administrative advantage, balanced by a predictable and manageable primary safety risk. The drug's ability to achieve more profound PTH reduction than the previous standard of care, cinacalcet, is well-supported by robust head-to-head clinical trial data. Its intravenous administration by healthcare providers in the dialysis clinic setting effectively eliminates the pervasive issue of patient non-adherence, translating its superior efficacy into greater real-world effectiveness. This must be weighed against its principal risk of hypocalcemia, an on-target effect that necessitates a rigorous protocol of laboratory monitoring and careful dose titration to ensure patient safety.

Established Role in Therapy

The established role for Etelcalcetide in clinical practice is as a powerful agent for achieving biochemical control in patients with moderate-to-severe SHPT. It is particularly valuable for patients who have not responded adequately to, are intolerant of, or are known to be non-adherent with oral therapies such as cinacalcet and vitamin D analogs. Its provider-administered nature makes it a reliable tool for nephrologists seeking to gain control over the complex mineral and bone metabolism in their most challenging patients.

Future Research and Unanswered Questions

Despite its proven biochemical efficacy, critical questions regarding the long-term clinical impact of Etelcalcetide remain. The most significant of these is whether its superior control of surrogate markers like PTH and FGF23 will translate into meaningful improvements in hard clinical outcomes, such as reduced rates of cardiovascular events, bone fractures, and all-cause mortality. The experience with cinacalcet in the EVOLVE trial, which showed only a modest and statistically non-significant benefit on its primary composite endpoint, has created a degree of uncertainty regarding the direct link between PTH reduction and improved patient survival, a point that has been central to cost-effectiveness debates.[32]

Future research must therefore focus on addressing these crucial gaps. Key areas for investigation include:

• Long-Term Outcome Trials: A large-scale, long-term clinical trial designed to assess the impact of Etelcalcetide on cardiovascular morbidity and mortality, as well as fracture rates, is needed to definitively establish its role in improving patient outcomes beyond laboratory values.
• Pediatric Use: The completion of ongoing Phase 3 trials in the pediatric population is essential to establish its safety and efficacy in children and adolescents on hemodialysis, a population with a high unmet medical need.[34]
• Bone and Vascular Health: Further elucidation of its effects on bone architecture and the progression of vascular calcification through studies like NCT03960437 and ETERNITY-ITA will provide a more complete understanding of its impact on the broader pathophysiology of CKD-MBD.[33]

The promising data on LVH regression and FGF23 reduction suggest that Etelcalcetide may offer benefits that extend beyond its primary indication. Confirming these benefits with robust, long-term outcome data will be the final step in defining its ultimate value in the nephrology therapeutic armamentarium.

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