Macimorelin

Macimorelin is a pseudotripeptide built from D-tryptophan and a modified tryptophan aldehyde, engineered for oral absorption and metabolic stability where the peptide GHRPs have neither. It stimulates GHS-R1a on pituitary somatotrophs and in the hypothalamus, producing a reproducible GH peak within 30 to 90 minutes. Its clinical role is entirely diagnostic: a maximally stimulated GH below 2.8 ng/mL confirms adult GH deficiency, with sensitivity around 87 percent and specificity around 96 percent against the insulin tolerance test, and a test-retest reproducibility of about 97 percent. It carries none of the hypoglycaemia risk that makes the insulin tolerance test dangerous in older patients or those with cardiac or seizure history.

Targets: GHS-R1a (ghrelin receptor), Pituitary somatotrophs

• · 0.5 mg per kg body weight as a single oral solution, reconstituted from granules in about 120 mL of water and drunk within 30 minutes. Serum GH is drawn at 30, 45, 60 and 90 minutes. A peak below 2.8 ng/mL confirms deficiency.

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• very commonDysgeusia - a bitter or metallic taste— The single most common complaint and part of why patients recognise the test.
• commonDizziness
• commonHeadache
• uncommonFatigue
• uncommonNausea
• uncommonQT interval prolongation— A labelled warning; avoid co-administration with other QT-prolonging drugs and consider an ECG in at-risk patients.
• uncommonHunger— Expected from a ghrelin-receptor agonist.

• Concomitant use of drugs that prolong the QT interval, unless they can be safely stopped beforehand.
• Known hypersensitivity to macimorelin.
• Recent use of strong CYP3A4 inducers, which reduce macimorelin exposure and can produce a false positive result.

• conflictQT-prolonging medicines — Additive QT risk; the label advises stopping them and allowing sufficient washout before testing.
• conflictStrong CYP3A4 inducers such as rifampicin, carbamazepine or St John's wort — Reduce macimorelin plasma levels and risk a false-positive GH deficiency diagnosis.
• conflictsomatropin — Exogenous GH must be stopped well before testing or the result is meaningless.
• cautionGlucocorticoids — Supraphysiological steroid doses blunt the GH response and can produce a false positive.

• · Serum GH at 30, 45, 60 and 90 minutes post-dose - this is the test itself.
• · ECG for QT interval in patients at cardiac risk.
• · Confirm the patient has fasted at least 8 hours; a fed state invalidates the result.

FDA and EMA approved as a diagnostic agent for adult growth hormone deficiency, prescription-only. Prohibited in sport under WADA S2 as a GH secretagogue.

• Garcia et al. 2018 JCEM, macimorelin as a diagnostic test for adult GH deficiency versus the insulin tolerance test (trial)
• Macrilen (macimorelin) FDA prescribing information (label)

Macimorelin is the only compound in this class whose entire clinical purpose is to produce a measurement rather than an effect. It is a GHS-R1a agonist engineered to survive the gut, and the diagnostic logic is straightforward: if the somatotroph population is intact, a maximal ghrelin-receptor stimulus produces a GH surge, and if it is not, it does not. The label's operating characteristics against the insulin tolerance test are worth stating precisely because they are commonly overstated. In the clinical study, a maximally stimulated serum GH below 2.8 ng/mL across the 30, 45, 60 and 90 minute timepoints confirms adult GH deficiency, with 74 percent positive agreement and 94 percent negative agreement with the ITT in the overall population. The 87 percent sensitivity and 96 percent specificity figures that circulate - and that appear in the Core record - come from the published primary analysis population in Garcia's paper rather than from the label's overall-population agreement numbers. Both are real; they are answering slightly different questions, and the label's numbers are the more conservative. The clinical case for macimorelin is not that it is more accurate than the insulin tolerance test - it is that the ITT deliberately induces hypoglycaemia, which is dangerous in older patients and contraindicated in anyone with cardiac disease or a seizure history, and macimorelin achieves comparable discrimination by drinking a solution. Two things can invalidate the test. Strong CYP3A4 inducers - rifampicin, carbamazepine, St John's wort - lower macimorelin exposure and can produce a false positive. Food does the same thing by a different route. The QT signal is modest but labelled: a thorough QT study found a mean placebo-adjusted QTcF increase of 9.6 msec at 4 hours after a supratherapeutic 2 mg/kg dose, with no clear dose dependence across the doses tested.

Almost every macimorelin failure is a preparation failure rather than a drug failure. A patient who ate breakfast produces a suppressed GH response and a false diagnosis of deficiency, because a liquid meal alone cuts exposure roughly in half. A patient on carbamazepine or St John's wort does the same. A patient who did not stop their GH produces an uninterpretable result. The oral solution must be consumed within 30 minutes of reconstitution and the remainder discarded. The dysgeusia - a strong bitter or metallic taste - is very common and is worth warning people about because it is unpleasant enough to cause someone to stop drinking partway through, which invalidates the dose. And the operating characteristics should be quoted honestly: 74 percent positive agreement against the ITT in the label's overall population is a meaningfully different claim from 87 percent sensitivity, and the difference matters when a patient's diagnosis rests on it.

1. —Single diagnostic administration — 0.5 mg per kg body weight as a single oral solution, reconstituted from granules in approximately 120 mL of water and consumed within 30 minutes. Serum GH is drawn at 30, 45, 60 and 90 minutes. There is no titration because there is no chronic dosing.

• GHS-R1a (ghrelin receptor), pituitary somatotroph — Full agonist with oral bioavailability; specific Ki not resolved here

  Reproducible GH surge peaking between 30 and 90 minutes. The magnitude of that surge is the diagnostic readout.

• GHS-R1a, hypothalamus — Not separately quantified

  Hunger, reported as an uncommon adverse effect and entirely expected from a ghrelin-receptor agonist.

• CYP3A4 (substrate) — Major metabolic pathway

  Strong inducers reduce exposure and risk a false-positive GH deficiency diagnosis. This is a labelled contraindication, not a theoretical interaction.

• Cardiac repolarisation — Not applicable

  Mean baseline- and placebo-adjusted QTcF increase of 9.6 msec (upper one-sided 95 percent confidence bound 11.4 msec) at 4 hours after a supratherapeutic 2 mg/kg dose.

• Garcia et al., macimorelin as a diagnostic test for adult GH deficiency 3 · 2018

  Agreement with the insulin tolerance test for the diagnosis of adult GH deficiency. The basis of the FDA approval in 2017 and the EMA approval in 2019.

Cmax at 0.5 to 1.5 hours; GH peaks between 30 and 90 minutes, which is why the sampling schedule is 30, 45, 60 and 90 minutes and the whole test takes 90 minutes. Terminal half-life is 4.1 hours. Dysgeusia is immediate. Dizziness and headache, where they occur, are within the first hour or two. There is no chronic timeline because there is no chronic use.

There is nothing to stack because there is nothing to treat. What matters is what must be removed before the test: QT-prolonging medicines need stopping with adequate washout, strong CYP3A4 inducers need stopping because they cause false positives, exogenous GH must be discontinued well in advance, and supraphysiological glucocorticoids blunt the GH response and can also produce a false positive. The one genuinely interesting question is whether macimorelin has any use as a chronic oral secretagogue - it is an orally active GHS-R1a agonist with a four-hour half-life, which is not far off MK-677's profile. Nobody has studied that, the cost per dose is enormous, and using it that way is off-label and unstudied.

Against the insulin tolerance test: comparable discrimination without deliberately inducing hypoglycaemia, which makes it usable in older patients and in anyone with cardiac disease or a seizure history where the ITT is contraindicated. That is the entire clinical argument and it is a good one. Against the glucagon stimulation test: macimorelin is faster, oral and better tolerated, though the glucagon test is far cheaper. Against every other compound in this class: macimorelin is the only one whose approval is for producing a number rather than an effect, and it should not be thought of as a treatment at all. Against MK-677 as an oral secretagogue: mechanistically similar - both orally active GHS-R1a agonists - but macimorelin has a 4-hour half-life, no chronic dosing data whatsoever, and costs orders of magnitude more per dose.

$1500–$4000/month. This is a cost per test, not per month - macimorelin is a single-administration diagnostic. US list pricing for a single Macrilen kit runs into the low thousands of dollars, which was a point of considerable controversy when it launched, because the insulin tolerance test it replaces costs almost nothing in drug terms. Figures are approximate.

• ?Volume of distribution, protein binding and clearance are not specified in the label and were not resolved elsewhere.
• ?Absolute oral bioavailability is not published.
• ?The Core record's 87 percent sensitivity and 96 percent specificity differ from the label's 74 percent positive and 94 percent negative agreement with the insulin tolerance test. Both figures appear in the literature and refer to different analysis populations; this discrepancy is real and unresolved here.
• ?The Core record's 97 percent test-retest reproducibility figure was not verified in this session.
• ?The exact pseudotripeptide structure was not resolved from a primary reference, so the sequence entry is unverified despite the confirmed molecular formula.
• ?There is no data at all on repeated or chronic administration, which is the only way anyone would use this outside a clinic.

• Macimorelin as a diagnostic test for adult GH deficiency Garcia JM, Biller BMK, Korbonits M, et al., Journal of Clinical Endocrinology and Metabolism, 2018 · PMID 29860473

  The validation study against the insulin tolerance test.

• MACRILEN (macimorelin) for oral solution - US prescribing information DailyMed, Novo Nordisk

  Source of the pharmacokinetics and operating characteristics used here: Cmax at 0.5 to 1.5 hours, terminal half-life 4.1 hours, CYP3A4 as the major pathway, the food effect (Cmax down 55 percent, AUC down 49 percent), the QTcF increase of 9.6 msec at supratherapeutic dose, and the 2.8 ng/mL cut-off with 74 percent positive and 94 percent negative agreement with the ITT.

• The macimorelin-stimulated growth hormone test for adult growth hormone deficiency diagnosis Agrawal V, Garcia JM, Expert Review of Molecular Diagnostics, 2014 · PMID 24834478

  Background on how the test was developed and why an oral alternative to the insulin tolerance test was worth building.

• Growth hormone stimulation tests in assessing adult growth hormone deficiency Yuen KCJ, Endotext, 2023 · PMID 27809446

  Further reading. Puts macimorelin in context against the insulin tolerance test, glucagon stimulation and the other provocation options.

• Macimorelin, PubChem compound record CID 9804938 PubChem

  Confirms molecular formula C26H30N6O3 and molecular weight 474.6, matching the Core record.