PwPepwise

Macimorelin

Growth Hormone

a.k.a. Macrilen

Oral ghrelin agonist

Macimorelin is an orally active synthetic peptide that stimulates the pituitary gland to release growth hormone (GH).

§Dosing at a glance

2 protocols · from the research
What it's forDoseHow oftenHowFor how long
Approved Adult Diagnostic Protocol (AGHD)0.5 mg/kg—OralTaken by mouth.—
Investigational Pediatric Protocol0.25 mg/kg—OralTaken by mouth.—

Approximate values pulled from the research — double-check before dosing.

§01Summary

Macimorelin is an orally active synthetic peptide that stimulates the pituitary gland to release growth hormone (GH) by mimicking the natural hunger hormone ghrelin. It is approved by both the FDA and the European Medicines Agency (EMA) as a diagnostic test for adult growth hormone deficiency (AGHD), a condition that can result from pituitary tumors, head trauma, or other causes affecting the pituitary gland11.

As a single oral dose, macimorelin reliably triggers GH release, and the resulting peak GH level in the blood is used to confirm or rule out GH deficiency. In pivotal clinical trials, macimorelin achieved 92% sensitivity and 96% specificity for diagnosing AGHD using a GH cutoff of 5.1 ng/mL, with 97% reproducibility on repeat testing1,3. Compared to the traditional insulin tolerance test (ITT) — the previous gold standard — macimorelin offers a substantially safer and more practical alternative, as the ITT requires inducing potentially dangerous low blood sugar whereas macimorelin is taken by mouth and carries no hypoglycemia risk1. Beyond its approved diagnostic use, researchers are actively exploring macimorelin's effects on other hormonal axes and its potential utility in pediatric GH deficiency testing8,14.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

Macimorelin (AEZS-130) is a synthetic, orally bioavailable peptidomimetic agonist of the growth hormone secretagogue receptor type 1a (GHSR-1a), also known as the ghrelin receptor. By binding and activating GHSR-1a in the hypothalamus and anterior pituitary, macimorelin mimics the endogenous ligand ghrelin, triggering a downstream signaling cascade primarily via Gαq/11-coupled phospholipase C activation, leading to inositol trisphosphate (IP3)-mediated intracellular calcium mobilization and protein kinase C activation. This results in the coordinated release of growth hormone from somatotroph cells of the anterior pituitary1,5.

GHSR-1a activation by macimorelin also stimulates hypothalamic neurons to release growth hormone-releasing hormone (GHRH), which acts synergistically with the direct pituitary effect to amplify GH secretion. At the approved 0.5 mg/kg oral dose, peak GH concentrations are typically achieved within 45–60 minutes post-administration1,14. Pharmacokinetic profiling in healthy adults demonstrates a median time to peak plasma concentration (tmax) of 0.5–0.75 hours and a mean elimination half-life of approximately 3.5 hours at therapeutic dosing, extending to approximately 8.3 hours at supratherapeutic doses (2.0 mg/kg), suggesting nonlinear pharmacokinetics at higher exposures5. Overall drug exposure (AUC and Cmax) is less than dose-proportional across the 0.5–2.0 mg/kg range, and paradoxically lower GH responses are observed at the 2.0 mg/kg dose compared to 0.5 and 1.0 mg/kg, possibly reflecting GHSR-1a desensitization or saturation at supraphysiological receptor occupancy5.

Beyond the somatotroph axis, GHSR-1a is expressed broadly across pituitary cell populations and the hypothalamic-pituitary axis. Consistent with this distribution, macimorelin produces transient increases in prolactin and free thyroxine (fT4), along with TSH suppression, in addition to non-dose-dependent increases in ACTH and cortisol4,5. These secondary hormonal effects reflect the broader receptor distribution of GHSR-1a but are transient and self-limiting in the context of single-dose diagnostic administration.

Notably, macimorelin does not appear to engage osmotic or glucoprivic pathways governing vasopressin (AVP/copeptin) secretion. Unlike glucagon or hypertonic saline stimulation, macimorelin produces no meaningful glucose perturbations and no increase in copeptin levels4,15. This mechanistic distinction confirms that ghrelin receptor agonism is pharmacologically decoupled from posterior pituitary AVP release in humans, and similarly does not stimulate oxytocin or neurophysin-I secretion13,20. In pediatric subjects, pharmacokinetic parameters scale comparably to adults, with dose-proportional Cmax and AUC across the 0.25–1.0 mg/kg range and GH peak times of 30–60 minutes, supporting translation of the adult pharmacodynamic model to younger populations14,18. Macimorelin's cardiac pharmacology includes QTcF interval prolongation, consistent with off-target hERG channel activity observed with some peptidomimetics, warranting consideration in patients with cardiac risk factors2,5.

§04Evidence & efficacy

Evidence base
78Studies
26Human
0Animal

Macimorelin is the first and only FDA- and EMA-approved oral growth hormone stimulation test for diagnosing adult GH deficiency11. In a pivotal multicenter RCT — the primary evidence base for regulatory approval — macimorelin achieved 92% sensitivity and 96% specificity against the ITT reference standard using a unified GH cutoff of 5.1 ng/mL, with 97% reproducibility on repeat testing and a test evaluability rate of 99% compared to 82% for the ITT1,3,7. Post hoc analysis of diagnostic performance across four cutpoints (2.8, 4.0, 5.1, and 6.5 ng/mL) confirmed that 5.1 ng/mL provides the optimal balance of sensitivity and specificity, with ROC AUC values consistently exceeding 0.99 regardless of age, BMI, or sex10,16. In an earlier validation study, macimorelin demonstrated non-inferiority to the arginine+GHRH reference test with an AUROC of 0.999.

GH stimulation is robust and consistent: at the approved 0.5 mg/kg dose, mean peak GH concentrations of approximately 31.9 ng/mL are achieved in healthy adults5, and GH peaks are observed at approximately 45–60 minutes post-dose in both adults and pediatric subjects14. Macimorelin also produces measurable increases in prolactin and free T4, and suppresses TSH4, though these are pharmacological effects rather than intended diagnostic endpoints.

Macimorelin does not stimulate copeptin/vasopressin release, ruling it out as a diagnostic tool for diabetes insipidus4,15. It also does not stimulate oxytocin or neurophysin-I in healthy adults13,20. In a separate preclinical context, macimorelin appears to reduce seizure frequency and duration in a pharmacoresistant epilepsy model, and this application is an area of active investigation19.

Pediatric diagnostic efficacy data are emerging: early-phase studies demonstrate dose-proportional pharmacokinetics and robust GH stimulation within 30–60 minutes across doses of 0.25–1.0 mg/kg in children and adolescents14,18, with a Phase 3 confirmatory pediatric trial currently underway8.

§05Safety

Macimorelin is generally well tolerated at the approved 0.5 mg/kg diagnostic dose. Across pivotal clinical trials in adults, no serious adverse events attributable to macimorelin were reported, and the drug was consistently described as well tolerated1,3,9. In a dedicated single-dose pharmacokinetic and pharmacodynamic study, treatment-emergent adverse events occurred in 35.7% of participants across all dose groups, but all were mild to moderate in severity and resolved spontaneously; headache was the most frequently reported drug-related adverse event5.

A clinically notable cardiac safety signal has been identified. A thorough QT/QTc study using a supratherapeutic dose of 2.0 mg/kg — four times the approved diagnostic dose — produced a maximum mean QTcF prolongation of 9.61 ms (90% CI: 7.81–11.41 ms), with the upper confidence interval bound exceeding the 10 ms regulatory threshold of concern at both the 3- and 4-hour timepoints2. At the approved 0.5 mg/kg dose, QTcF prolongation of approximately 10–11 ms was also observed in the pharmacokinetic study across all active dose groups5. An asymptomatic QT interval prolongation was reported as a drug-related serious adverse event in the early phase validation trial9. Caution is warranted in patients with pre-existing cardiac risk factors or those taking concomitant QT-prolonging medications.

Beyond GH stimulation, macimorelin has been shown to transiently increase prolactin and free T4 while suppressing TSH4, and to produce transient, non-dose-dependent increases in ACTH and cortisol5. These pituitary axis effects are self-limiting in the context of a single diagnostic dose but represent pharmacological activity extending beyond the GH axis.

In pediatric dose-escalation studies (n=24, ages 2 to <18 years), no macimorelin-related adverse events were reported across doses of 0.25–1.0 mg/kg, supporting the tolerability of the compound in younger patients, though the sample size is small14,18.

By comparison, the conventional insulin tolerance test carries a known risk of severe hypoglycemia and is contraindicated in patients with seizure disorders, ischemic heart disease, and other conditions — risks that macimorelin avoids entirely1,3.

§06History

Macimorelin was synthesized as part of a broader program to develop orally active, non-peptide and peptidomimetic ghrelin receptor agonists capable of stimulating GH secretion — a research area that emerged following the discovery of the GHSR-1a receptor in the 1990s and the subsequent identification of ghrelin as its endogenous ligand in 1999. The compound, originally designated AEZS-130, was developed by Æterna Zentaris as a diagnostic tool to address the practical limitations of existing GH stimulation tests, particularly the insulin tolerance test, which requires induced hypoglycemia and is contraindicated in vulnerable patient populations.

An initial validation study published in 2013 established macimorelin's diagnostic accuracy against the arginine+GHRH reference standard, reporting an AUROC of 0.99 and a diagnostic GH cutoff of approximately 2.7 ng/mL9. A pivotal multicenter RCT subsequently compared macimorelin head-to-head against the ITT in a large multinational cohort, providing the primary evidence base for regulatory approval1,6. The FDA granted approval of macimorelin (brand name Macrilen) in December 2017 as the first oral GH stimulation test for diagnosing AGHD in the United States, followed by EMA authorization in January 201911. The optimal diagnostic GH cutoff was subsequently refined from the initially studied 2.8 ng/mL to 5.1 ng/mL based on post hoc analyses, which improved sensitivity while maintaining specificity1,10,16. Research has since expanded to investigate macimorelin's utility in pediatric GHD diagnosis8,14 and to characterize its broader pharmacological profile4,5, with active clinical development continuing across multiple settings.

§07References