A Comprehensive Pharmacological and Clinical Monograph on Corticorelin

1.0 Drug Identification and Overview

Corticorelin is a synthetic polypeptide that has occupied two distinct and divergent roles in modern medicine: one as an approved diagnostic agent for complex endocrine disorders and the other as an investigational therapeutic for a severe neurological complication of brain cancer. A precise understanding of Corticorelin necessitates a clear and consistent differentiation between its two primary synthetic forms, which possess different chemical structures, clinical applications, and regulatory histories. This report will meticulously delineate these forms to provide a comprehensive and unambiguous analysis of the drug.

1.1 Nomenclature and Synonyms

The nomenclature surrounding Corticorelin is complex, reflecting its dual identity and its basis as a synthetic version of an endogenous hormone.

• Primary Generic Name: The internationally recognized nonproprietary name for the human synthetic form is Corticorelin.[1]
• Synonyms: A variety of synonyms are used in scientific literature and databases. These include Corticoliberin, human corticotropin-releasing factor (hCRF), and the more general Therapeutic Corticotropin-Releasing Factor. The abbreviations CRF and CRH are also commonly used to refer to both the endogenous hormone and its synthetic analogs.[2]
• Brand Names: The human formulation of Corticorelin, investigated for its therapeutic potential in treating peritumoral brain edema, was developed under the brand name Xerecept.[6] In contrast, the ovine (sheep-derived) analog, which was commercialized as a diagnostic agent, was marketed under the brand name Acthrel.[8] In certain European markets, nationally authorized versions were available under names such as Crh Ferring and Stimu-Acth.[10]

1.2 Key Identifiers

To ensure precise identification across global databases and scientific literature, the following identifiers are critical:

• DrugBank ID: The primary entry for Corticorelin (human form) is DB05394.[1]
• CAS Number: The Chemical Abstracts Service (CAS) number for the human form of Corticorelin is 86784-80-7.[1] For completeness, it is noted that other CAS numbers, such as 9015-71-8 and the deprecated 86297-72-5, are also associated with this substance in various databases.[2] The distinct ovine triflutate salt form (Acthrel) is identified by CAS number 121249-14-7.[12]
• Other Identifiers: Additional identifiers include the Unique Ingredient Identifier (UNII) 305OE8862Y, PubChem Compound ID (CID) 16186200, ChEMBL ID CHEMBL2107324, KEGG Drug ID D03905, and NCI Thesaurus Code C394.[3]

1.3 General Description and Classification

Corticorelin is a synthetic 41-amino-acid polypeptide designed to be structurally and functionally analogous to the endogenous neurohormone, corticotropin-releasing factor (CRF). Natural CRF is synthesized within the parvocellular neurosecretory cells of the paraventricular nucleus of the hypothalamus and serves as the primary regulator of the stress response cascade.[1]

• Drug Type/Modality: While categorized broadly as a Small Molecule in some databases [1], Corticorelin is more accurately described as a peptide pharmaceutical or protein pharmaceutical. This classification is fundamental to understanding its complex synthesis, inherent instability, route of administration, and pharmacokinetic profile.[3]
• Pharmacological Class: The Medical Subject Headings (MeSH) classification places Corticorelin within the category of Hormones.[2] The World Health Organization's Anatomical Therapeutic Chemical (ATC) classification system assigns it the code V04CD04, under the parent class "Tests for pituitary function," reflecting the primary approved use of its ovine analog.[1]

1.4 Distinction Between Human and Ovine Formulations

The dual identity of "Corticorelin" in the medical lexicon stems from the development of two distinct molecules for separate clinical purposes. This distinction is paramount, as conflating the two forms leads to a misrepresentation of their respective clinical utility, safety profiles, and regulatory standing.

• Corticorelin (Human): This synthetic peptide (CAS 86784-80-7) is chemically identical to the endogenous 41-amino acid human CRF.[6] Its development, under the name Xerecept, was focused on a therapeutic indication: the management of peritumoral brain edema (PBE), a serious complication of brain tumors.[6]
• Corticorelin Ovine Triflutate: This molecule (CAS 121249-14-7) is a synthetic analog of sheep (ovine) CRF, formulated as a trifluoroacetate salt to improve stability.[12] It differs from the human form in its amino acid sequence.[13] This version was successfully developed and marketed as a diagnostic agent under the brand name Acthrel. Its approved use was to aid clinicians in the differential diagnosis of ACTH-dependent Cushing's syndrome by assessing the responsiveness of the pituitary gland.[9]

The separate development pathways of these two molecules are a direct consequence of their structural differences. The ovine form, Acthrel, achieved regulatory approval and was used clinically for over two decades as a niche diagnostic tool before its eventual discontinuation. In contrast, the human form, Xerecept, was pursued for a much more complex and challenging therapeutic indication but has not, to date, received marketing approval.[3] This divergence illustrates how subtle variations in peptide structure can lead to profoundly different clinical and commercial trajectories, highlighting the unique challenges and opportunities in peptide drug development.

2.0 Physicochemical and Structural Properties

The biological activity and pharmacological characteristics of Corticorelin are intrinsically linked to its specific chemical structure and physical properties. This section details the molecular blueprint of the human form of Corticorelin (DB05394).

2.1 Molecular Formula and Weight

• Molecular Formula: The chemical formula for human Corticorelin is consistently reported as $C_{208}H_{344}N_{60}O_{63}S_2$.[3]
• Molecular Weight: The average molecular weight is approximately 4757.5 g/mol. Various sources provide precise values with minor variations, including 4757.52 g/mol [11], 4757.45 g/mol [4], and 4757.46 g/mol.[20] The computed monoisotopic mass is 4754.5000146 Da.[2] Some commercial suppliers list a molecular weight of 4575.5 g/mol, which appears to be a consistent typographical error but is noted here for completeness.[21]

2.2 Amino Acid Sequence and Peptide Structure

Corticorelin is a linear polypeptide composed of 41 amino acids, mirroring its endogenous human counterpart.[3]

• One-Letter Amino Acid Sequence: The sequence is written as: SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII.2
• Full Amino Acid Sequence: The complete primary structure is: H-Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH₂.2
• Key Structural Feature: A critical feature of the synthetic peptide is the amidation of the C-terminal isoleucine residue, denoted by -NH₂. This modification is a common strategy in peptide drug design to mimic the native structure and to increase metabolic stability by protecting the C-terminus from degradation by carboxypeptidases, thereby prolonging the peptide's biological half-life and activity.
• Three-Dimensional Structure: Due to its significant size (41 residues) and inherent flexibility, a stable three-dimensional conformer for Corticorelin has not been generated or determined. This is typical for linear peptides of this length, which often exist as an ensemble of conformations in solution and adopt a more defined structure only upon binding to their specific receptor.[2]

2.3 Physical Characteristics and Solubility

• Appearance: In its pharmaceutical form, Corticorelin is supplied as a white to off-white lyophilized (freeze-dried) solid or powder.[4]
• Solubility: The peptide is soluble in dimethyl sulfoxide (DMSO).[19] Its solubility in aqueous solutions is limited but can be enhanced. Reports indicate a water solubility of approximately 1.10 mg/mL, which can be increased to as high as 16.66 mg/mL with the application of sonication and warming.[4] This information is crucial for proper reconstitution and administration in both clinical and laboratory settings.
• Storage and Stability: For long-term preservation of its integrity, Corticorelin should be stored at -20°C in a dry, dark environment. For short-term storage (days to weeks), a temperature of 0-4°C is acceptable.[4]

Table 1: Key Identifiers and Physicochemical Properties of Corticorelin (Human)
Property	Value / Identifier
Generic Name	Corticorelin
DrugBank ID	DB05394
CAS Number	86784-80-7 (Note: 9015-71-8 and 86297-72-5 are also associated)
Molecular Formula	$C_{208}H_{344}N_{60}O_{63}S_2$
Average Molecular Weight	~4757.5 g/mol
Amino Acid Sequence	H-SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH₂
Sequence Length	41 amino acids
Key Synonyms / Brand Names	hCRF, Corticoliberin, Xerecept

3.0 Pharmacology and Mechanism of Action

Corticorelin exhibits a complex pharmacological profile characterized by two distinct and functionally independent mechanisms of action. Its primary, well-characterized effect is the stimulation of the neuroendocrine stress axis, which forms the basis of its diagnostic utility. Its secondary, therapeutically investigated effects involve direct actions on the vasculature and tumor microenvironment, which are independent of its endocrine function.

3.1 Primary Mechanism: Hypothalamic-Pituitary-Adrenal (HPA) Axis Stimulation

As a synthetic analog of corticotropin-releasing factor, Corticorelin's principal mechanism of action is to mimic the physiological role of endogenous CRF in initiating the HPA axis cascade.[6]

1. Pituitary Stimulation: When administered systemically, Corticorelin travels to the anterior lobe of the pituitary gland. There, it binds to specific receptors on the surface of corticotroph cells.[1]
2. ACTH Release: This binding event stimulates the synthesis and secretion of adrenocorticotropic hormone (ACTH) from the corticotrophs into the bloodstream.[2]
3. Adrenal Stimulation: Circulating ACTH then acts on the adrenal cortex, stimulating the production and release of cortisol and other adrenal steroids.[5]
4. Negative Feedback: The resulting increase in plasma cortisol levels exerts negative feedback at the levels of both the pituitary and the hypothalamus, inhibiting further release of ACTH and CRF, respectively. This tightly regulated feedback loop is a hallmark of the HPA axis.[5]

This well-defined, dose-dependent stimulation of the HPA axis is the pharmacological principle that allowed for the development of the corticorelin stimulation test as a diagnostic tool.

3.2 Secondary Mechanisms: Anti-Edema and Antitumor Effects

During its investigation as a therapeutic agent for peritumoral brain edema (PBE), a second, distinct mechanism of action was identified. This effect is crucially described as being independent of adrenal gland function, meaning it is not mediated by the downstream release of cortisol.[2]

• Anti-Edema Effect: Corticorelin appears to exert a direct effect on the cerebral vasculature to combat vasogenic edema. The proposed mechanism involves impeding the pathological flow of fluid from blood vessels into surrounding brain tissue. It is thought to achieve this by reducing vascular leakage and preserving the integrity of endothelial cells that form the blood-brain barrier.[2] This direct vascular action is the basis for its potential as a steroid-sparing alternative to dexamethasone in the treatment of PBE.
• Antitumor and Antiangiogenic Effects: Preclinical evidence suggests that Corticorelin may also possess direct antitumor properties. This is hypothesized to occur through the suppression of tumor vascularization by reducing the expression of Vascular Endothelial Growth Factor (VEGF), a key signaling protein in angiogenesis.[5] This anti-VEGF activity was observed in preclinical models of human brain tumors and other solid tumors, where Corticorelin showed antitumor effects both as a monotherapy and in combination with the antiangiogenic agent bevacizumab.[19]

3.3 Receptor Binding and Cellular Pathways

Corticorelin mediates its diverse physiological effects through binding to two main subtypes of corticotropin-releasing factor receptors, CRHR1 and CRHR2, which are members of the G protein-coupled receptor superfamily.[20] The functional selectivity of Corticorelin arises from the differential expression and signaling of these receptor subtypes in various tissues.

• CRHR1: This receptor is highly expressed on the corticotroph cells of the anterior pituitary. The binding of Corticorelin to CRHR1 is primarily responsible for mediating the stimulation of the HPA axis and the subsequent release of ACTH.[5]
• CRHR2: This receptor subtype is believed to mediate the adrenal-independent effects of Corticorelin. The proposed antiangiogenic and antitumor effects, involving the downregulation of VEGF, are thought to be triggered by the activation of CRHR2 on tumor or endothelial cells.[5]

This functional divergence is the core pharmacological principle behind the development of Corticorelin (Xerecept) as a therapeutic agent. The goal was to leverage the beneficial anti-edema effects, likely mediated by CRHR2, while minimizing the systemic side effects associated with potent and sustained activation of the HPA axis via CRHR1, which would lead to hypercortisolism. This strategy aimed to uncouple the desired anti-inflammatory/anti-edema properties from the broad, often deleterious, systemic effects of corticosteroids.

3.4 Pharmacodynamics: Effects on ACTH, Cortisol, and Other Peptides

The pharmacodynamic effects of intravenously administered Corticorelin are rapid and dose-dependent.

• ACTH Response: In healthy individuals, plasma ACTH levels begin to rise within 2 minutes of injection, reaching peak concentrations between 10 and 15 minutes post-administration.[17]
• Cortisol Response: The increase in plasma cortisol follows the ACTH surge, with levels beginning to rise within 10 minutes and peaking between 30 and 60 minutes.[17]
• Other Peptides: Corticorelin administration also stimulates the release of other peptides derived from the same precursor molecule as ACTH, pro-opiomelanocortin (POMC). This results in a concomitant and prolonged release of β- and γ-lipotropins and β-endorphin.[17]
• Dose-Response Relationship: As the dose of Corticorelin is increased, the elevation in plasma ACTH and cortisol becomes more sustained. At higher doses, a biphasic response has been observed, with a second, smaller peak occurring 2 to 3 hours after the initial injection.[17]

4.0 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Corticorelin, which describes its movement into, through, and out of the body, is characteristic of a peptide-based drug. The most detailed data available pertains to the ovine triflutate form (Acthrel) administered intravenously for diagnostic purposes, which provides a reliable model for the general behavior of this class of molecules in the human body.

4.1 Administration and Absorption

• Route of Administration: Corticorelin is administered via intravenous (IV) injection or infusion.[17] This route is necessary because, as a peptide, it would be degraded by proteases in the gastrointestinal tract if taken orally.
• Absorption: The IV route ensures that absorption is bypassed, leading to immediate and 100% bioavailability in the systemic circulation. This is reflected in the rapid onset of its pharmacodynamic effects, with plasma ACTH levels rising within 2 minutes of the injection.[17]

4.2 Volume of Distribution and Plasma Protein Binding

• Volume of Distribution (Vd): The mean volume of distribution for immunoreactive corticorelin (IR-corticorelin) has been determined to be 6.2 ± 0.5 L.[17] This is a relatively small Vd, indicating that the drug's distribution is largely restricted to the plasma and extracellular fluid compartments, with limited penetration into deeper tissues.
• Plasma Protein Binding: Corticorelin does not appear to bind specifically to any circulating plasma proteins.[17] This unbound state means that the entire circulating concentration of the drug is pharmacologically active and available to interact with its target receptors.

4.3 Metabolism and Biological Half-Life

• Metabolism: The precise metabolic pathways have not been fully elucidated in the provided materials. However, consistent with its peptide nature, Corticorelin is expected to undergo rapid metabolism, primarily in the liver and plasma, through degradation by proteolytic enzymes (peptidases). This process breaks the peptide down into smaller, inactive peptide fragments and constituent amino acids.[25]
• Biological Half-Life: The elimination of Corticorelin from the plasma is rapid and follows a biexponential decay pattern, indicating a two-compartment model of distribution and elimination.[17]
• The initial, rapid distribution phase (alpha half-life) is 11.6 ± 1.5 minutes.
• The subsequent, slower elimination phase (beta half-life) is 73 ± 8 minutes. This short half-life is typical for endogenous peptide hormones and necessitates administration via continuous infusion when a sustained therapeutic effect is desired, as was the case in the clinical trials for peritumoral brain edema.17

4.4 Route of Excretion

• Excretion: The final route of elimination for the inactive metabolic fragments of Corticorelin is primarily through the kidneys, with excretion into the urine.[25]
• Metabolic Clearance Rate: The approximate metabolic clearance rate for IR-corticorelin is calculated to be 95 ± 11 L/m²/day.[17]

Table 2: Summary of Pharmacokinetic Parameters (Corticorelin Ovine Triflutate)
Parameter	Value
Route of Administration	Intravenous
Alpha Half-Life (Distribution)	11.6 ± 1.5 minutes
Beta Half-Life (Elimination)	73 ± 8 minutes
Mean Volume of Distribution	6.2 ± 0.5 L
Metabolic Clearance Rate	95 ± 11 L/m²/day
Plasma Protein Binding	Not specifically bound

5.0 Clinical Applications and Efficacy

The clinical history of Corticorelin is a tale of two distinct applications: one a successful, approved diagnostic tool and the other a promising but ultimately unapproved therapeutic agent. This section examines the evidence and application for each.

5.1 Diagnostic Use: The Corticorelin Stimulation Test for Hypercortisolism

The primary, and only, approved clinical application for a corticorelin product was the use of corticorelin ovine triflutate (Acthrel) as a diagnostic agent in endocrinology.[9]

• Indication: The corticorelin stimulation test was indicated for the differential diagnosis of ACTH-dependent hypercortisolism. After a patient was confirmed to have high cortisol levels driven by excess ACTH, the test was used to distinguish between a pituitary source of ACTH (i.e., a pituitary adenoma, known as Cushing's disease) and an ectopic source (i.e., a non-pituitary tumor producing ACTH).[11]
• Test Principle and Interpretation: The test is based on the differential responsiveness of pituitary adenomas versus ectopic tumors to CRH stimulation.
• Pituitary Adenomas (Cushing's Disease): The corticotroph cells in a pituitary adenoma, while dysfunctional, typically retain their CRH receptors and some degree of responsiveness. Therefore, administration of Corticorelin leads to a significant increase in both plasma ACTH and cortisol levels. This positive response is indicative of Cushing's disease.[17]
• Ectopic ACTH Syndrome: Tumors outside the pituitary that secrete ACTH (e.g., small-cell lung cancer) do not typically express CRH receptors and their ACTH production is autonomous. Consequently, administration of Corticorelin results in little to no change in plasma ACTH or cortisol levels. This blunted or absent response points to an ectopic source of ACTH.[11]
• Procedure: The standard protocol for the test involves the intravenous administration of a 1 mcg/kg dose of corticorelin ovine triflutate over 30 to 60 seconds. Venous blood samples for ACTH and cortisol measurement are collected at baseline (e.g., -15 minutes and 0 minutes) and at specified intervals post-injection (e.g., 15, 30, and 60 minutes) to assess the dynamic response of the HPA axis.[17]

5.2 Investigational Therapeutic Use: Peritumoral Brain Edema (PBE)

The human form of Corticorelin (Xerecept) was the subject of significant clinical investigation as a novel therapeutic agent for PBE.

• Rationale: PBE is a form of vasogenic edema caused by the disruption of the blood-brain barrier by a brain tumor. The standard treatment, high-dose corticosteroids like dexamethasone, is effective but associated with severe systemic side effects (e.g., myopathy, hyperglycemia, immunosuppression) that can be debilitating.[6] Corticorelin was investigated as a potential steroid-sparing agent because of its unique, adrenal-independent mechanism for reducing edema. The goal was to provide the anti-edema benefit without the toxicity of systemic steroids.[6]
• Clinical Evidence: Early-phase clinical trials and preclinical studies were promising. They demonstrated that human Corticorelin was reasonably well-tolerated and appeared effective in reducing PBE and its associated neurological signs and symptoms.[6] These studies reported that Corticorelin offered a "distinct advantage" over classical corticosteroids, with fewer and milder side effects.[6] This promising data led to the initiation of a large, multicenter, randomized, placebo-controlled Phase III clinical trial (NCT00088166). This pivotal study was designed to definitively assess the efficacy of human Corticorelin (hCRF) as a dexamethasone-sparing agent for controlling symptoms of PBE in patients with malignant brain tumors.[3]

The clinical development path of Corticorelin highlights a common challenge in the pharmaceutical industry. While the diagnostic agent (Acthrel) successfully navigated the regulatory process for a well-defined, niche indication, the therapeutic agent (Xerecept) faced a much higher bar for approval. Despite a strong mechanistic rationale and encouraging early data, it failed to reach the market. This outcome was likely due to a combination of factors inherent to late-stage development: the immense difficulty and expense of demonstrating superior efficacy and safety against an established, inexpensive standard of care like dexamethasone in a large Phase III trial; and potential challenges related to the consistent, large-scale manufacturing of a complex peptide. This trajectory serves as a potent example of the "valley of death" in drug development, where promising candidates can falter before reaching patients due to the formidable scientific, regulatory, and commercial hurdles of late-stage clinical research.

5.3 Other Investigational Areas

Beyond PBE, Corticorelin has been explored in other contexts. It has been studied in the broader treatment of brain cancer and other neurological disorders, with preclinical data showing direct antitumor activity.[2] It has also been utilized as a research tool in basic science studies, for example, to investigate stress biomarkers in healthy volunteers.[30]

6.0 Safety Profile, Adverse Effects, and Tolerability

The safety profile of Corticorelin is well-documented, primarily from its use as a diagnostic agent and in clinical trials. The adverse effects are generally transient and dose-dependent.

6.1 Common and Infrequent Adverse Events

Adverse events are categorized by their observed frequency in clinical settings:

• Most Common (>10% of patients): The most frequently reported side effect is a transient flushing of the face, neck, and upper chest.[11]
• Common (1% to 10% of patients): Other common effects include a transient sensation of warmth and sensory disturbances such as dysosmia (distorted sense of smell) and dysgeusia (distorted sense of taste). Dyspnea (shortness of breath) is also reported in this frequency range.[11]
• Infrequent (0.1% to 1% of patients): Less common side effects include cardiovascular changes like hypotension (low blood pressure) and tachycardia (increased heart rate). Other reported effects include a cold sensation in the throat, a sudden urge to urinate, and dizziness.[11]
• Rare (<1% of patients): Rare but serious events have been observed, including asystole (cardiac arrest), seizure, vomiting, and xerostomia (dry mouth).[27]

6.2 Serious Adverse Events and Dose-Dependent Toxicity

The severity and likelihood of adverse events are strongly correlated with the administered dose.

• Dose-Dependency: While the standard diagnostic dose of 1 mcg/kg is generally well-tolerated, higher doses are associated with a significantly increased risk of serious adverse events. For this reason, doses exceeding 1 mcg/kg are not recommended.[18]
• Cardiovascular Events: At higher doses, Corticorelin has been associated with transient but significant cardiovascular effects, including marked hypotension, tachycardia, loss of consciousness, and in rare cases, asystole.[18] Administering the drug as a 30-second infusion rather than a rapid bolus injection can mitigate some of these effects.[31]
• Pituitary Apoplexy: A particularly serious and rare adverse event is pituitary apoplexy, which involves hemorrhage or infarction of the pituitary gland. This has been reported in patients with pre-existing, often undiagnosed, pituitary tumors. This represents a critical risk, as the strong stimulation of the gland by Corticorelin can precipitate this medical emergency.[11]
• Hypersensitivity Reactions: Allergic reactions can occur, ranging from mild urticaria (hives) and flushing to more severe angioedema involving swelling of the tongue, lips, and face, which can compromise the airway.[31]

6.3 Warnings, Precautions, and Contraindications

• Contraindications: The official manufacturer's label for Acthrel did not list any absolute contraindications.[27] However, due to the risk of a severe interaction, co-administration with heparin is strongly advised against and is considered a de facto contraindication.[27]
• Precautions:
• Corticosteroid Use: Recent or concurrent use of corticosteroids (e.g., dexamethasone) can blunt the pituitary's response to Corticorelin, potentially leading to a false-negative test result. This is a critical consideration when interpreting the results of the stimulation test.[27]
• Hypersensitivity: When using the ovine-derived formulation (Acthrel), caution should be exercised in patients with a known or suspected hypersensitivity to sheep proteins.[27]
• Carcinogenicity: Long-term studies to evaluate the carcinogenic potential of Corticorelin have not been conducted.[27]

6.4 Use in Specific Populations

• Pregnancy: Corticorelin is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women, and it is not known if the drug can cause fetal harm. It should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.[27]
• Lactation: It is not known whether Corticorelin is excreted in human milk. Because many drugs are, caution should be exercised when administering it to a nursing woman.[27]
• Pediatrics: While experience is limited, available studies have not identified pediatric-specific problems that would limit its usefulness in children. The standard weight-based dose of 1 mcg/kg has been used in pediatric studies.[31]

7.0 Clinically Significant Drug Interactions

The clinical utility and safety of Corticorelin can be significantly affected by co-administered medications. The interactions are primarily pharmacodynamic, altering the drug's intended effect on the HPA axis.

7.1 Contraindicated Combinations

• Heparin: The co-administration of heparin with Corticorelin is contraindicated. A possible interaction between the two drugs has been associated with a major hypotensive reaction and asystole. The mechanism for this interaction is unknown. Clinically, this means that heparin solutions must not be used to maintain the patency of an intravenous cannula during a corticorelin stimulation test.[27]

7.2 Interactions Leading to Reduced Efficacy (Pharmacodynamic Antagonism)

Several classes of drugs can blunt or inhibit the stimulatory effect of Corticorelin on the pituitary, potentially confounding the results of the diagnostic test.

• Corticosteroids: This is the most significant interaction. Systemic, topical, or inhaled corticosteroids (e.g., dexamethasone, mometasone, beclomethasone) suppress the HPA axis via negative feedback. Pre-treatment with these agents will blunt the plasma ACTH response to Corticorelin, potentially leading to a false-negative result (i.e., making a pituitary adenoma appear unresponsive, mimicking an ectopic source).[8]
• Other Antagonists: The physiological effects of Corticorelin can also be attenuated by other drug classes, including antihistamines, antiserotonergics, and oxytocin.[11]

7.3 Interactions Leading to Amplified Effects

• Vasopressin: Vasopressin and its synthetic analogues act synergistically with Corticorelin to stimulate ACTH release from the pituitary. Co-administration can therefore lead to an amplified or exaggerated response, which could complicate the interpretation of the diagnostic test.[11]

Table 3: Corticorelin Drug Interactions
Interacting Agent	Severity Level	Mechanism and Clinical Effect	Management Recommendation
Heparin	Contraindicated	Unknown mechanism. Increases the risk of severe hypotension and asystole.	Do not co-administer. Do not use heparin to maintain IV cannula patency during the test.
Corticosteroids (e.g., Dexamethasone, Mometasone)	Monitor Closely	Pharmacodynamic antagonism. Suppress the HPA axis, blunting the ACTH response to stimulation.	Discontinue corticosteroid therapy prior to testing if possible. Interpret results with caution in patients with recent or current use.
Vasopressin (and its analogues)	Monitor Closely	Pharmacodynamic synergism. Potentiates the ACTH-releasing effect of Corticorelin.	Be aware of potential for an exaggerated response. Avoid co-administration during diagnostic testing if possible.
Antihistamines, Antiserotonergics, Oxytocin	Monitor Closely	Pharmacodynamic antagonism. May reduce the effects of Corticorelin.	Be aware of potential for a blunted response. Interpret test results with caution.

8.0 Regulatory Status and Development History

The regulatory history of Corticorelin is a story of two distinct products on divergent paths. The ovine form (Acthrel) achieved marketing approval as a diagnostic agent in several countries before being discontinued, while the human form (Xerecept) remains an investigational product despite extensive clinical research.

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

• Approval and Marketing: The FDA granted Orphan Drug Designation to corticorelin ovine triflutate (Acthrel) on November 24, 1989, for its use in differentiating the causes of ACTH-dependent Cushing's syndrome.[9] Following this, Ferring Pharmaceuticals received marketing approval for Acthrel on May 23, 1996, under Biologics License Application (BLA) 020162.[9] The product was marketed for over two decades for its specific diagnostic indication.
• Discontinuation: In late September 2020, Ferring, the sole manufacturer of Acthrel, discontinued the product. The reason cited for the withdrawal from the market was "manufacturing sourcing issues".[35] This was a logistical failure rather than a removal due to safety or efficacy concerns. The FDA's Purple Book database now lists the marketing status of Acthrel as "Disc." (Discontinued).[34]
• Investigational Status: The human Corticorelin analog, Xerecept, has undergone extensive clinical investigation, including a Phase III trial for peritumoral brain edema, but it has not been approved by the FDA and remains an investigational drug.[3]

The discontinuation of Acthrel underscores a critical vulnerability in the pharmaceutical supply chain, particularly for complex biologic drugs serving niche markets. The withdrawal was not prompted by new adverse safety data or a re-evaluation of its efficacy but by a failure in the manufacturing and supply process. Corticorelin, as a 41-amino acid peptide, requires a far more complex and specialized manufacturing process than a traditional small-molecule drug. This complexity, combined with a small target patient population (those undergoing differential diagnosis for Cushing's syndrome), creates a fragile economic and logistical ecosystem. The failure of a single component in this supply chain can lead to the complete withdrawal of a medically necessary product. This event left a significant void in the diagnostic armamentarium for endocrinologists, forcing a greater reliance on alternative, often more invasive or less specific, diagnostic procedures. It serves as a powerful case study on how non-clinical factors can impact drug availability and patient care.

8.2 European Medicines Agency (EMA) and National Authorizations

• EMA Status: Corticorelin has not received a centralized marketing authorization from the European Medicines Agency. Searches of the EMA's public databases for centrally authorized products do not yield an approval for any form of Corticorelin.[1]
• National Authorizations: Despite the lack of a central EMA approval, Corticorelin has been authorized at the national level in several individual European Union member states. A 2015 EMA document pertaining to a periodic safety update review identified nationally authorized products containing Corticorelin. These included products marketed as "Crh Ferring" in Austria, Germany, and the Netherlands, and as "Stimu-Acth" in France.[1] This demonstrates a fragmented regulatory landscape for the drug within Europe, with availability dependent on individual national agency decisions.

8.3 Therapeutic Goods Administration (TGA) - Australia

• Approval Status: Documents obtained through Freedom of Information requests indicate that the TGA granted an approval for a "Corticotrophin Releasing Hormone (Corticorelin)" injection on January 27, 2012.[38] The documents list the product as approved.[39] However, the specific nature of this approval—whether it was a full registration for marketing (an AUST R number) or an approval under a special access or clinical trial scheme—is not fully clarified by the provided materials. A definitive determination of its current status would require a direct search of the Australian Register of Therapeutic Goods (ARTG), a function not available within the source documents.[40]

8.4 Key Clinical Trials and Development Milestones

The development history of Corticorelin is marked by several key clinical trials that defined its potential applications.

• NCT00088166: This was the pivotal Phase III study for the therapeutic candidate Xerecept (human Corticorelin). It was a randomized, double-blind, dexamethasone-sparing study designed to compare hCRF to a placebo for controlling symptoms associated with peritumoral brain edema in patients with malignant brain tumors.[3] The ultimate outcome of this trial was critical to its development path and likely determined why it did not proceed to regulatory approval.
• NCT01673087: This was a Phase I basic science trial that used Corticorelin as a tool to study stress biomarkers, demonstrating its utility in a research setting beyond its primary diagnostic or therapeutic goals.[30]

9.0 Concluding Analysis and Future Outlook

Corticorelin stands as a fascinating case study in pharmaceutical development, embodying both the precision of targeted diagnostics and the unfulfilled promise of a novel therapeutic strategy. Its legacy is twofold, defined by the successful clinical application of one analog and the stalled development of another, despite a compelling scientific rationale.

9.1 Synthesis of Corticorelin's Dual Role

The history of Corticorelin is a story of two divergent paths. As corticorelin ovine triflutate (Acthrel), it was a successful diagnostic tool. Its mechanism of action—a direct and predictable stimulation of the HPA axis—was perfectly suited for a diagnostic test designed to probe the integrity and origin of ACTH secretion. The test provided clinicians with a clear, pharmacologically-driven method to differentiate Cushing's disease from ectopic ACTH syndrome, a critical distinction for guiding patient treatment.

In contrast, as synthetic human Corticorelin (Xerecept), it represented a sophisticated therapeutic hypothesis. The goal was to leverage a secondary, adrenal-independent mechanism to treat peritumoral brain edema, offering a steroid-sparing alternative to dexamethasone. This approach was scientifically elegant, aiming to uncouple the desired anti-edema effect from the broad and often toxic side effects of systemic corticosteroids. However, despite promising early-phase data, this therapeutic ambition was never realized in a marketed product. This failure to translate a complex secondary mechanism into an approved therapy, juxtaposed with the success of the simpler diagnostic application, highlights the immense challenges of developing drugs for complex diseases against an established standard of care.

9.2 Implications of Acthrel's Discontinuation

The withdrawal of Acthrel from the market in 2020 for manufacturing reasons, not for safety or efficacy concerns, created a tangible clinical gap. Endocrinologists lost a valuable and specific tool for the differential diagnosis of ACTH-dependent hypercortisolism. In its absence, clinicians must rely more heavily on other diagnostic modalities, such as high-dose dexamethasone suppression testing, which can have its own limitations, or more invasive and technically demanding procedures like bilateral inferior petrosal sinus sampling (BIPSS). The discontinuation of Acthrel serves as a stark reminder that the availability of essential medicines, particularly those for rare conditions, can be fragile and dependent on logistical and commercial factors beyond their clinical value.

9.3 Future Research Directions and Potential

While Corticorelin itself may now be largely a legacy drug, the biological pathways it targets remain an area of intense scientific interest. The CRF system, including its receptors CRHR1 and CRHR2, is deeply implicated in a wide range of physiological and pathological processes beyond the HPA axis, including anxiety, depression, inflammation, and neoplastic growth.

The story of Corticorelin provides a valuable foundation for future drug development. The challenges encountered in developing a peptide therapeutic like Xerecept may spur research into more stable, non-peptide small-molecule agonists or antagonists that can more selectively target CRHR1 or CRHR2. Such molecules could offer novel therapeutic approaches for a host of conditions:

• CRHR1 antagonists are being investigated for stress-related psychiatric disorders like anxiety and depression.
• CRHR2-selective agonists could revisit the therapeutic hypothesis of Xerecept, potentially offering a more potent or stable way to control vasogenic edema or inhibit tumor angiogenesis without activating the HPA axis.

In conclusion, Corticorelin's journey from a hypothalamic hormone to a marketed diagnostic and an investigational therapeutic has significantly advanced our understanding of the CRF system. While its direct clinical use has ended, the scientific questions it helped to frame and the biological targets it validated continue to inspire new avenues of pharmacological research, ensuring its enduring relevance in the quest for novel treatments for endocrine, neurological, and oncological diseases.

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