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Macimorelin

Macimorelin

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Oral non-peptide peptidomimetic GHS-R1a (ghrelin receptor) agonist; FDA-approved as a diagnostic test for adult growth hormone deficiency — pharmacologically related to MK-677/ibutamoren.

Quick Facts

Property Value
Also Known As Macrilen, AEZS-130, ARD-07, EP-01572, macimorelin acetate
Category GH Axis / Diagnostic
Sequence Non-peptide peptidomimetic (D-Trp-Ala-Trp-D-Phe-Lys-NH2 modified backbone)
Molecular Weight ~535 Da (non-peptide small molecule)
Molecular Formula C26H30F3N5O3
PubChem CID 9832404
Administration Oral (single dose dissolved in water)
Typical Dose Range 0.5 mg/kg oral (single diagnostic dose)
Half-Life ~4.1 hours
Storage Room temperature; single-use sachets
FDA Status Approved (2017) — Macrilen for diagnosis of adult growth hormone deficiency (AGHD)
WADA Status Not specifically listed (diagnostic agent, not for performance enhancement)

Mechanism of Action

Macimorelin is a synthetic, orally bioavailable, non-peptide peptidomimetic that acts as an agonist at the growth hormone secretagogue receptor type 1a (GHS-R1a), also known as the ghrelin receptor. GHS-R1a is a G protein-coupled receptor (GPCR) expressed primarily on somatotroph cells in the anterior pituitary, where its activation triggers a Gq/PLC/IP3/calcium signaling cascade that stimulates growth hormone (GH) release.

NOTE: Despite being called a "peptidomimetic," macimorelin is a non-peptide small molecule (~535 Da) that mimics the structure and receptor-binding properties of ghrelin, the endogenous GHS-R1a ligand. It belongs to the same pharmacological class as MK-677 (ibutamoren), another non-peptide GHS-R1a agonist. However, while MK-677 is used off-label for chronic GH elevation and body composition effects, macimorelin is designed and approved exclusively for single-dose diagnostic use.

After oral administration (0.5 mg/kg), macimorelin is absorbed from the GI tract, reaches peak plasma concentration within ~0.5-0.75 hours, and stimulates pituitary GH release. In subjects with intact pituitary GH reserve, serum GH rises robustly, typically peaking at 30-45 minutes. In patients with adult GH deficiency (AGHD), the GH response is blunted or absent. A peak GH level below 2.8 ng/mL at any timepoint (30, 45, 60, or 90 minutes) indicates GH deficiency (PMID: 29860473).

The diagnostic utility of macimorelin rests on the same principle as the GH secretagogue class: GHS-R1a activation provides a reliable, quantifiable stimulus for pituitary GH secretion that can differentiate normal GH reserve from deficiency. The advantage over the insulin tolerance test (ITT) — the previous gold standard — is safety (no hypoglycemia risk), convenience (oral administration, no IV access), and reproducibility (94% test-retest agreement vs ~70-80% for ITT) (PMID: 33320108).

Macimorelin is metabolized primarily via CYP3A4; strong CYP3A4 inhibitors may increase its exposure and should be avoided or accounted for.

Key Research Areas

  1. Pivotal Phase 3 diagnostic validation — In 157 subjects, macimorelin achieved 87% sensitivity, 96% specificity, and 9% misclassification rate at a 2.8 ng/mL GH cut-point compared to ITT as reference standard (PMID: 29860473)
  2. Phase 2 proof-of-concept — First clinical validation of oral GH stimulation testing; 82% sensitivity, 92% specificity at 2.7 ng/mL cut-point (PMID: 23559086)
  3. Diagnostic test reproducibility — Pooled analysis confirmed 94% test-retest agreement, superior to ITT reproducibility; BMI may modestly affect test performance (PMID: 33320108)
  4. Childhood GH deficiency — Under investigation for diagnosing childhood-onset GHD

Evidence Level Summary

Evidence Type Count Notes
Systematic reviews 0 —
Human RCTs 2 Phase 2 (n=68) and Phase 3 (n=157) diagnostic accuracy studies
Human observational 1 Pooled post-hoc sensitivity/specificity analysis
Animal in vivo 0 —
In vitro 0 —

Clinical Applications

  • Sarcopenia — Diagnostic tool for confirming GH deficiency that may contribute to age-related sarcopenia
  • Adult growth hormone deficiency — FDA-approved diagnostic test

Protocols Using This Peptide

  • No current vault protocols use macimorelin. It is a single-dose diagnostic agent, not a therapeutic.
  • Related therapeutic GHS-R1a agonists in the vault:
    • Ipamorelin — Selective peptide GHS-R1a agonist (therapeutic use)
    • MK-677 — Non-peptide GHS-R1a agonist (chronic oral use, not FDA-approved)
    • GHRP-6 — Peptide GHS-R1a agonist

Ageless Peps Products

  • Not sold by Ageless Peps. Macimorelin is an FDA-approved prescription diagnostic agent (Macrilen) available through specialty pharmacies for use in clinical endocrinology settings.

Dosing Reference

FDA-Approved Dosing

Indication Dose Route Frequency Duration Source
Diagnosis of adult GH deficiency 0.5 mg/kg Oral (dissolved in 120 mL water) Single dose One-time test FDA label

Test Protocol

  1. Patient fasts overnight (minimum 8 hours)
  2. Baseline GH blood draw
  3. Administer macimorelin 0.5 mg/kg dissolved in 120 mL water; drink within 30 seconds
  4. Blood draws for GH at 30, 45, 60, and 90 minutes post-dose
  5. Peak GH <2.8 ng/mL at any timepoint = GH deficiency confirmed
  6. Peak GH >=2.8 ng/mL = GH deficiency excluded

Cycling

Not applicable. Macimorelin is a single-dose diagnostic agent. Repeated testing has been validated with high reproducibility (94% agreement) but is not routinely needed.

Contraindications & Safety

  • Contraindications: Known hypersensitivity to macimorelin or any excipient
  • Cautions: CYP3A4 interactions — avoid strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) and inducers within 7 days of test; these may alter macimorelin exposure and produce false results
  • Common side effects: Dysgeusia (bitter/metallic taste, most common), dizziness, headache, nausea, fatigue (all transient, single-dose context)
  • Drug interactions: CYP3A4 inhibitors/inducers; drugs that affect GH secretion (e.g., somatostatin analogs, glucocorticoids, GH itself) — may produce false-positive or false-negative results
  • Pregnancy/nursing: No data; diagnostic use only
  • Special populations: BMI >30 may slightly attenuate GH response (consider BMI-adjusted interpretation); limited data in children (under investigation)
  • QTc prolongation: Mild, transient QTc prolongation observed at supratherapeutic doses; use caution in patients at risk for QTc prolongation

Synergistic Combinations

  • Not applicable. Macimorelin is a standalone diagnostic agent.
  • Pharmacological family context: Macimorelin, MK-677 (ibutamoren), and ipamorelin all target GHS-R1a but serve different clinical roles:
    • Macimorelin — Single-dose diagnostic (FDA-approved)
    • MK-677 — Chronic oral GH elevation (research/off-label, not FDA-approved)
    • Ipamorelin — Peptide GHS-R1a agonist for therapeutic GH optimization (SubQ, research use)

Related Research

PMID Title Year Study Type
23559086 Macimorelin (AEZS-130)-Stimulated GH Test: Validation (Phase 2) 2013 RCT
29860473 Macimorelin as a Diagnostic Test for Adult GH Deficiency (Phase 3) 2018 RCT
33320108 Sensitivity and Specificity of the Macimorelin Test for AGHD 2021 Observational

References

Related

#peptide #gh-axis #fda-approved #not-sold #oral