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Macimorelin

Also known as AEZS-130, EP-01572, JMV 1843, Macrilen, Ghryvelin

Oral ghrelin receptor agonist approved as a single-dose diagnostic test for adult GH deficiency.

clinically proven Growth hormone approved drug

At a glance

Category
Growth hormone
Status
approved drug
Route
oral, as a reconstituted solution taken after an overnight fast of at least 8 hours
Half-life
mean terminal half-life 4.1 hours after a single oral 0.5 mg/kg dose in healthy subjects 1
Onset
Maximum GH levels are observed between 30 and 90 minutes after administration 1; the whole test is complete in 90 minutes
Molecular weight
474.6 g/mol (free base); 510.0 g/mol as the acetate salt
Sequence
A pseudotripeptide: 2-methylalanyl-N-[(1R)-1-(formylamino)-2-(1H-indol-3-yl)ethyl]-D-tryptophanamide. It is a peptidomimetic rather than a conventional peptide, which is what allows oral absorption

Prescription medicine. Initial US approval 2017 (Macrilen), for the diagnosis of adult growth hormone deficiency 1; approved in the European Union in January 2019 as Ghryvelin for the same purpose 5. It is a diagnostic agent, not a treatment: a single dose is given once, in a supervised setting, and it has no approved therapeutic use 1. Development as a treatment for cancer cachexia was discontinued.

Doping status: Prohibited at all times (WADA S2, growth hormone secretagogues)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Macimorelin is an orally active agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a), the receptor for ghrelin. It belongs pharmacologically to the same family as ipamorelin, hexarelin, the GHRPs and MK-677, but unlike those it is a licensed medicine with a defined, narrow purpose.

GHS-R1a is expressed on pituitary somatotrophs and on hypothalamic neurons. Activation couples through Gq to phospholipase C, raising intracellular inositol trisphosphate and calcium and triggering GH exocytosis. At the hypothalamic level it also amplifies GHRH release and suppresses somatostatin tone, which removes the brake described in the somatostatin entry. The combination of a direct pituitary effect and a reduction in somatostatin inhibition produces a much larger GH pulse than a GHRH analogue alone.

Being a peptidomimetic with a stabilised backbone, macimorelin survives the gut and is absorbed orally with a half-life of roughly four hours. That is the entire clinical point: the historical reference standard for diagnosing adult GH deficiency is the insulin tolerance test, which requires induced hypoglycaemia, an intravenous line, repeated blood draws over several hours and constant medical supervision, and is contraindicated in patients with coronary disease or a seizure disorder. Macimorelin replaces that with a single drink and four blood samples.

The test works because a healthy pituitary with adequate somatotroph reserve responds to GHS-R1a stimulation with a large GH pulse, while a deficient pituitary does not. The approved cut-off is a stimulated GH of 2.8 ng/ml in the US label; the validation study identified 5.1 ng/ml as the value giving the best balance of sensitivity and specificity 2, and different regulators and later analyses have used different thresholds. This is a genuine and ongoing point of debate — a cut-off is a trade-off between missing deficient patients and over-diagnosing healthy ones, and the right value depends on pretest probability and on the assay used.

Because the test depends on a functional GH axis, anything that suppresses that axis invalidates it. Somatostatin analogues, exogenous growth hormone, recent glucocorticoids and untreated hypothyroidism all blunt the response and produce a false positive for deficiency.

What the research shows

The evidence base is small in absolute terms but well designed for its purpose: a randomised, two-way crossover trial directly against the insulin tolerance test, which is what regulators required and what secured approval in both the US and the EU. It is not evidence that macimorelin does anything therapeutically useful — that was never claimed and was never demonstrated.

Research in humans

Garcia et al. (Journal of Clinical Endocrinology & Metabolism, 2018) conducted a multicentre, open-label, randomised two-way crossover study comparing single-dose oral macimorelin with the insulin tolerance test in adults with a range of pretest probability of GH deficiency. Agreement between the two tests was asymmetric: negative agreement was 95.38 per cent but positive agreement only 74.32 per cent, so the tests concurred far more readily that a patient was not deficient than that they were. Sensitivity was approximately 87 per cent and specificity approximately 96 per cent at the chosen cut-off; a post hoc analysis applying the same 5.1 ng/ml cut-off to both tests raised positive agreement to 82 per cent and sensitivity to 92 per cent 2. A separate 2021 analysis in Endocrine Connections re-examined sensitivity and specificity across different thresholds 3. Earlier work established the validation of macimorelin (AEZS-130) as a stimulation test. In cancer cachexia, macimorelin raised GH and IGF-1 in early trials but development for that indication did not continue.

Animal and lab research

Preclinical pharmacology established GHS-R1a agonism, oral bioavailability and dose-dependent GH release, and supported the safety profile submitted for approval. Given that this is a single-dose diagnostic agent with human validation data, the animal work is of limited independent interest.

Caveats. The validation study is a single pivotal trial with a modest sample size, and the choice of cut-off remains contested — the label value and the value the authors identified as optimal differ. Performance depends on the GH assay used, and assay standardisation across laboratories is imperfect. Obesity blunts GH responses to all secretagogues, and the test has not been separately validated across the full range of body mass index. It has not been validated in children in most jurisdictions. It cannot be used at all in patients on somatostatin analogues or growth hormone. Cost is significantly higher than the insulin tolerance test, which is the main reason uptake has been slower than the convenience argument would suggest.

What it is used for

  • Approved: diagnosis of adult growth hormone deficiency, as a single-dose oral stimulation test 15. The label adds a limitation of use: safety and diagnostic performance have not been established in subjects with a BMI above 40 kg/m2 1
  • Not approved and not used: any therapeutic application. Macimorelin is not a treatment for GH deficiency, cachexia, body composition or anything else 1
  • Investigational, discontinued: cancer anorexia-cachexia syndrome

Dosing

Dose
A single oral dose of 0.5 mg/kg body weight, taken once as a reconstituted solution.
Frequency
one dose, once, as a diagnostic procedure — there is no repeated or ongoing dosing
Route
oral solution, after an overnight fast of at least 8 hours
Duration
The procedure lasts 90 minutes. Blood samples for growth hormone are drawn at 30, 45, 60 and 90 minutes after administration.
  • This dose comes directly from the FDA-approved Macrilen prescribing information and is the entire approved use of the drug 1.
  • The patient must fast for at least 8 hours beforehand 1. Food matters quantitatively: a liquid meal decreased macimorelin Cmax by 55 per cent and AUC by 49 per cent 1.
  • The US label states that a maximally stimulated serum GH of less than 2.8 ng/ml across the 30, 45, 60 and 90 minute timepoints confirms adult growth hormone deficiency 1. The validation study identified 5.1 ng/ml as the threshold with the best balance of sensitivity and specificity 2; the applicable cut-off depends on jurisdiction, assay and clinical context.
  • Growth hormone products must be discontinued at least one week before the test, and deficiencies in sex hormones, thyroid hormone or glucocorticoids must be adequately replaced beforehand 1. Drugs directly affecting pituitary GH secretion — somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors such as aspirin or indomethacin — are to be avoided 1.
  • Macimorelin prolongs the QT interval, and the label directs avoiding concomitant drugs known to prolong QT, with sufficient washout beforehand 1.
  • Doses circulating outside medical use, on the premise that macimorelin can be taken repeatedly as an oral secretagogue, have no basis in any published study. There is no safety, efficacy or tolerability data for repeated dosing in humans.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Macrilen diagnostic test for adult growth hormone deficiency

approved product information

Source: FDA prescribing information, MACRILEN, 2017

Before the testfast for at least 8 hours; growth hormone therapy stopped at least one week beforehand, strong CYP3A4 inducers discontinued, and any sex hormone, thyroid or glucocorticoid deficiency adequately replaced first
Single dose0.5 mg/kg body weight as a reconstituted oral solution at 0.5 mg/ml, drunk within 30 seconds (one 60 mg pouch in 120 ml of water up to 120 kg body weight, two pouches in 240 ml above that)
30, 45, 60 and 90 minutes after the dosevenous blood samples drawn for growth hormone determination

This is the entire approved use of the drug: one dose, once, as a diagnostic procedure - there is no repeated or ongoing schedule. The US label reads a maximally stimulated GH below 2.8 ng/ml across those four timepoints as confirming adult growth hormone deficiency. The prepared solution must be used within 30 minutes and the remainder discarded.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
60 mg macimorelin per single-use packet of granules
Solvent
cold drinking water — the packet contents are dispersed in water immediately before the test
Storage
Packets are stored refrigerated at 2-8 °C in the original carton until use. The reconstituted solution is used within 30 minutes and any unused portion discarded — it is not kept.

Worked example

For a 70 kg patient the dose is 35 mg. A 60 mg packet is dispersed in 120 ml of cold water and stirred gently for about 2 to 3 minutes, giving 0.5 mg/ml; the required volume is then measured out, in this example 70 ml. Two separate time limits apply and they are easily confused: the prepared solution must be used within 30 minutes of preparation, and the patient drinks the measured volume within 30 seconds. The remainder is discarded.

This is a hospital or clinic preparation, not a self-administered one. The calculation is a genuine source of dosing error: the packet contains 60 mg but the reconstituted solution is 0.5 mg/ml, so the volume administered depends on the patient's weight. Follow only the preparation instructions in the product leaflet.

This is taken by mouth, so there is no syringe volume to work out.

Safety

Side effects

  • Dysgeusia — a metallic or unpleasant taste; the most commonly reported reaction, in 4.5 per cent of the 154 dosed subjects 1
  • Dizziness — 3.9 per cent 1
  • Headache — 3.9 per cent 1
  • Fatigue — 3.9 per cent 1
  • Nausea — 3.2 per cent 1
  • Hunger — 3.2 per cent, reflecting the drug's ghrelin-receptor agonism 1
  • Sinus bradycardia — 1.3 per cent 1
  • Diarrhoea — 1.9 per cent 1
  • Nasopharyngitis and upper respiratory tract infection — 1.3 and 1.9 per cent respectively 1
  • QT interval prolongation — the safety issue that shapes the label. A thorough QT study found a mean placebo-adjusted QTcF increase of 9.6 msec (upper 95 per cent CI 11.4 msec) at a supra-therapeutic 2 mg/kg dose, with similar prolongation at 0.5 and 1 mg/kg, and the label warns this can lead to torsade de pointes 1
  • Feeling hot — 1.3 per cent 1
  • Hyperhidrosis — 1.3 per cent 1

Do not use if

  • The FDA label lists no formal contraindications at all 1. What follows are the label's warnings and pre-test requirements, not contraindications in the regulatory sense.
  • Concomitant drugs that prolong the QT interval — antipsychotics, moxifloxacin, class IA and class III antiarrhythmics among them — are to be avoided, with sufficient washout beforehand, because of the risk of torsade de pointes 1
  • Concomitant strong CYP3A4 inducers (carbamazepine, phenytoin, rifampin, St John's wort, enzalutamide, mitotane, bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide) substantially reduce macimorelin plasma levels and can produce a false positive result; they must be discontinued with adequate washout 1
  • Current growth hormone treatment: growth hormone products must be discontinued at least one week beforehand 1
  • Drugs that directly affect pituitary GH secretion — somatostatin, insulin, glucocorticoids and cyclooxygenase inhibitors such as aspirin or indomethacin — should not be used concomitantly 1
  • Deficiencies in sex hormones, thyroid hormone or glucocorticoids must be adequately replaced before the test 1
  • Recent-onset hypothalamic disease may give a false negative, because macimorelin acts downstream of the hypothalamus and can release stored pituitary GH reserves; repeat testing may be warranted 1
  • Safety and diagnostic performance have not been established above a BMI of 40 kg/m2 1
  • Not established in children in most jurisdictions
  • Not for use as a treatment of any kind

Interactions

CYP3A4 is the major enzyme metabolising macimorelin 1. Strong CYP3A4 inducers — the label names carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St John's wort, bosentan, efavirenz, etravirine, modafinil, armodafinil and rufinamide — reduce macimorelin plasma concentrations and may lead to false positive results; they must be discontinued with sufficient washout 1. Drugs known to prolong the QT interval must not be co-administered, since macimorelin itself prolongs QT and the combination may lead to torsade de pointes 1. Growth hormone products must be discontinued at least one week beforehand 1. Drugs directly affecting pituitary GH secretion (somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors such as aspirin or indomethacin), drugs that transiently elevate GH (clonidine, levodopa, insulin), and drugs that blunt the GH response (muscarinic antagonists such as atropine, anti-thyroid medication such as propylthiouracil) are all to be avoided 1. Food interferes with absorption: a liquid meal reduced Cmax by 55 per cent and AUC by 49 per cent, hence the fasting requirement 1.

Sources