ACTHREL- corticorelin ovine triflutate injection, powder, lyophilized, for solution
Ferring Pharmaceuticals Inc.

For intravenous injection only DIAGNOSTIC USE ONLY


ACTHREL® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder, containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH (hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for corticorelin ovine triflutate is described below:

Ser-Gin-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH2 ∙xCF2 COOH

whereas x =4 — 8.

The empirical formula of corticorelin ovine is C205 H339 N59 O63 S with a molecular weight of 4670.35 Daltons.

ACTHREL® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The preparation is intended for intravenous administration.



In normal subjects, intravenous administration of corticorelin results in a rapid and sustained increase of plasma ACTH levels and a near parallel increase of plasma cortisol. In addition, intravenous administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related proopiomelanocortin peptides β- and γ-lipotropins (β -and γ-LPH) and β-endorphin (β -END). A number of dose-response studies have been performed on normal subjects using a range of corticorelin doses. In one study, doses of corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers. Blood samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations. There was a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol. The threshold dose was 0.03 mcg/kg, the half-maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.

Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of ≥0.3 mcg/kg and reached peak levels after 10-15 minutes. Plasma cortisol levels increased within 10 minutes and reached peak levels at 30 to 60 minutes. As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection. Similar results were found in another study using 0.3, 3.0, and 30 mcg/kg doses. The duration of mean plasma ACTH increase after injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively. The effect on plasma cortisol was similar, but more prolonged. Because there are differences in basal levels and peak response levels following a.m. or p.m. administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation test be carried out at the same time of day as the original evaluation.

Baseline ACTH and cortisol levels are usually higher in the morning. Pooled ACTH values from normal unstressed subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were 11 ± 3 mcg/dL in the a.m. and 4 ± 2 mcg/dL in the p.m. The normal unstressed person has about seven to ten secretory episodes of ACTH each day. Most of them occur in the early morning hours and are responsible for the morning plasma cortisol surge. The following figure shows the daily circadian rhythm of ACTH and cortisol secretions in a normal unstressed person. Insulin, plasma renin activity, prolactin, and growth hormone release are not affected by corticorelin administration in humans.

(click image for full-size original)

Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increased plasma ACTH concentrations to a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours, comparable to those levels observed in patients with major depression, but less than levels noted in Cushing’s disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however, continued to elicit the expected ACTH and cortisol responses.

Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.

The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin administered to normal volunteers in the morning and the evening are given below. These values were obtained by combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.

The following table is to be used only as a general guide.

Basal Concentrations and Peak Responses of ACTH and Cortisol in Normal Subjects after 1 mcg/kg or 100 mcg of ACTHREL®
Time of DayNo. of SubjectsACTH Concentration mean (range) pg/mLCortisol Concentration mean (range) mcg/dL
a.m.14328 (16-65)68 (39-114)11 (8-13)21 (17-25)
p.m.709 (8-13)30 (25-42)4 (2-6)16 (15-18)


Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve. Plasma half-lives for IR-corticorelin are 11.6 ± 1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate metabolic clearance rate of 95 ± 11 L/m2 /day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound specifically by a circulating plasma protein.


ACTHREL® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing’s syndrome.

Differential Diagnosis

There are two forms of Cushing’s syndrome:

  1. ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing’s disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and,

  2. ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas).

After the establishment of hypercortisolism consistent with the presence of Cushing’s syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion.

The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:

  • High basal plasma ACTH plus high basal plasma cortisol (20 — 40 mcg/dL). ACTHREL® injection (1 mcg/kg) results in:
    1. Increased plasma ACTH levels
    2. Increased plasma cortisol levels Diagnosis: Cushing’s disease (ACTH of pituitary origin)
  • High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 — 40 mcg/dL). ACTHREL® injection (1 mcg/kg) results in:
    1. Little or no response of plasma ACTH levels
    2. Little or no response of plasma cortisol levels
    Diagnosis: Ectopic ACTH syndrome
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