Macimorelin
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
- 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)
- 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)
- Diagnostic test reproducibility — Pooled analysis confirmed 94% test-retest agreement, superior to ITT reproducibility; BMI may modestly affect test performance (PMID: 33320108)
- 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
- Patient fasts overnight (minimum 8 hours)
- Baseline GH blood draw
- Administer macimorelin 0.5 mg/kg dissolved in 120 mL water; drink within 30 seconds
- Blood draws for GH at 30, 45, 60, and 90 minutes post-dose
- Peak GH <2.8 ng/mL at any timepoint = GH deficiency confirmed
- 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
- PMID: 23559086 — Garcia et al., JCEM 2013 (Phase 2 validation)
- PMID: 29860473 — Garcia et al., JCEM 2018 (Phase 3 pivotal)
- PMID: 33320108 — Garcia et al., Endocrine 2021 (pooled diagnostic analysis)
Related
- Peptide Index
- Condition Index
- Research Index
- MK-677 — Related non-peptide GHS-R1a agonist (chronic use)
- Ipamorelin — Related peptide GHS-R1a agonist
- GHRP-6 — Related peptide GHS-R1a agonist
- Sermorelin — GHRH analog (different mechanism, same GH axis)
#peptide #gh-axis #fda-approved #not-sold #oral