In a mouse model of IHKA, macimorelin (5 mg/kg, intraperitoneally, twice daily for 2 weeks) decreases the frequency and length of seizures [2].

Animal/Disease Models: Intrahippocampal kainic acid (IHKA) mouse model [2]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection twice a day for two weeks.
Experimental Results: The number and duration of seizures were Dramatically diminished during treatment, but there was no anti-epileptogenic or disease-modifying effect.

Absorption, Distribution and Excretion
Masimorelin is a novel synthetic auxin-releasing peptide agonist readily absorbed from the gastrointestinal tract. In adults with auxin-releasing peptide deficiency (AGHD), after oral administration of 0.5 mg/kg masimorelin for at least 8 hours on an empty stomach, peak plasma concentration (Cmax) is reached between 0.5 and 1.5 hours. Higher doses may result in dose-proportionate increases in plasma concentration. Liquid meals reduced the Cmax and AUC of masimorelin by 55% and 49%, respectively. The mean central compartment volume of distribution after a single oral administration of 0.5 mg/kg masimorelin was 5,733.4 ± 565.7 L. The mean clearance to fraction of absorption (Cl/F) ratio after a single oral administration of 0.5 mg/kg masimorelin was 37,411.0 ± 4,554.6 mL/min.

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Metabolism/Metabolites
According to an in vitro human liver microsomal study, masimorelin is primarily metabolized via CYP3A4.

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Biological Half-Life
The mean terminal half-life (T1/2) after a single oral dose of 0.5 mg/kg body weight of masimorelin is 4.1 hours in healthy subjects.

[1]. Macimorelin as a Diagnostic Test for Adult GH Deficiency. J Clin Endocrinol Metab. 2018 Aug 1;103(8):3083-3093.

[2]. Translational potential of the ghrelin receptor agonist macimorelin for seizure suppression in pharmacoresistant epilepsy. Eur J Neurol. 2021 Sep;28(9):3100-3112.

[3]. Ali SA, Garcia JM. Randomized clinical trial of the novel oral ghrelin mimetic macimorelin in the treatment of cancer cachexia: study design and preliminary results. Endocr Rev. 2013;34:.

Macimorelin is a novel, orally administered, active growth hormone-releasing peptide mimic that stimulates growth hormone (GH) secretion for the diagnosis of adult growth hormone deficiency (AGHD). More specifically, Macimorelin is a peptide growth hormone secretagogue (GHS) that acts as an agonist of the growth hormone secretagogue receptor (GHS-R1a), increasing growth hormone levels in a dose-dependent manner. Growth hormone secretagogues (GHS) represent a new class of drugs with potential for a variety of clinical applications. They can be used to treat growth retardation in children and cachexia associated with chronic diseases such as HIV and cancer. Growth hormone (GH) is typically closely associated with linear growth during childhood. Growth hormone deficiency leads to adult growth hormone deficiency and is accompanied by symptoms such as increased fat mass (especially in the abdomen), reduced lean body mass, osteopenia, dyslipidemia, insulin resistance, and/or impaired glucose tolerance. Furthermore, individuals with adult growth hormone deficiency (AGHD) may be more prone to cardiovascular complications due to structural and functional alterations. Risk factors for AGHD include a history of childhood-onset growth hormone deficiency, a history of hypothalamic/pituitary disease, a history of surgery or radiation therapy to these areas, a history of head trauma, or evidence of other pituitary hormone deficiencies. Although various treatment options exist, such as growth hormone replacement therapy, the detection and diagnosis of AGHD face challenges due to the lack of panhypopituitarism, low serum insulin-like growth factor-I (IGF-I) levels, and atypical clinical symptoms. Diagnosis of AGHD requires at least one growth hormone stimulation test and confirmation by biochemical markers. Macimorelin exhibits good stability and oral bioavailability, and possesses comparable affinity to the endogenous ligand auxin-releasing peptide receptor, thus demonstrating clinical value. In clinical studies involving healthy subjects, macimorelin stimulated growth hormone release in a dose-dependent manner and was well-tolerated. Developed by Aeterna Zentaris, macimorelin was approved by the U.S. Food and Drug Administration (FDA) in December 2017 for use as an oral solution under the brand name Macrilen. Macimorelin is a growth hormone secretagogue receptor agonist. Its mechanism of action is as a growth hormone secretagogue receptor agonist. Macimorelin is an orally synthesized ghrelin analogue with potential anti-cachexia activity. After oral administration, Macimorelin mimics endogenous ghrelin by stimulating appetite and binds to the growth hormone secretagogue receptor (GHSR) in the central nervous system, thereby mimicking the growth hormone-releasing effect of pituitary ghrelin. Stimulation of growth hormone secretion increases the level of insulin-like growth factor-I (IGF-I), which may further stimulate protein synthesis. In addition, auxin-releasing peptides reduce the production of pro-inflammatory cytokines, which may play a direct role in cancer-related anorexia. See also: Macimorelin acetate (its active ingredient).

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Drug Indications
Indicated for the diagnosis of growth hormone deficiency (AGHD) in adults.
FDA Label
This medicine is for diagnostic use only. GHRYVELIN is indicated for the diagnosis of adult growth hormone deficiency (GHD).
Diagnosis of Growth Hormone Deficiency

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Mechanism of Action
Agroxin-releasing peptide is an endogenous ligand of the growth hormone secretagogue receptor (also known as the auxin-releasing peptide receptor (GHS-R1a)). Upon receptor activation, auxin-releasing peptide increases the secretion of growth hormone (GH). Massimorelin mimics the action of auxin-releasing peptide by stimulating GH release. As a synthetic agonist, it activates growth hormone secretagogue receptors present in the pituitary gland and hypothalamus.

C26H30N6O3

474.55

474.237

381231-18-1

Macimorelin acetate;945212-59-9

9804938

Typically exists as solid at room temperature

1.3±0.1 g/cm3

948.6±65.0 °C at 760 mmHg

527.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.676

2.64

6

4

9

35

761

2

CC(C(N[C@@H](C(N[C@@H](NC=O)CC1=CNC2=CC=CC=C12)=O)CC3=CNC4=CC=CC=C34)=O)(N)C

UJVDJAPJQWZRFR-DHIUTWEWSA-N

InChI=1S/C26H30N6O3/c1-26(2,27)25(35)31-22(11-16-13-28-20-9-5-3-7-18(16)20)24(34)32-23(30-15-33)12-17-14-29-21-10-6-4-8-19(17)21/h3-10,13-15,22-23,28-29H,11-12,27H2,1-2H3,(H,30,33)(H,31,35)(H,32,34)/t22-,23-/m1/s1

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)