Macimorelin
Also known as: AEZS-130, EP01572, macimorelin acetate, Macrilen
Orally active ghrelin receptor agonist (growth hormone secretagogue); synthetic peptidomimetic; GHS-R1a agonist; diagnostic pharmaceutical
What it is
Macimorelin (brand name Macrilen) is used by endocrinologists to diagnose growth hormone deficiency in adults. It is taken as a single oral drink before blood draws, replacing the need for intravenous insulin infusions or other invasive tests. Adults with suspected pituitary or hypothalamic disease are the primary candidates for testing.
The scientific side
macimorelin is a synthetic, orally bioavailable peptidomimetic that acts as a selective 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 expressed primarily in the hypothalamus and pituitary that normally responds to the endogenous hormone ghrelin to stimulate pulsatile growth hormone (GH) release from anterior pituitary somatotrophs. Cryo-electron microscopy studies of the GHSR-macimorelin complex at 2.63 Å resolution have revealed that macimorelin occupies a bifurcated binding pocket within the receptor, divided by a conserved salt bridge between residues E124 (3.33) and R283 (6.55), enabling high-affinity engagement of the Gq/11 signaling cascade. Upon oral administration, macimorelin is absorbed from the gastrointestinal tract with a time to maximum plasma concentration (Tmax) of approximately 0.5–0.75 hours at the approved 0.5 mg/kg dose, and achieves a terminal elimination half-life of approximately 3.5 hours. GHS-R1a agonism at the pituitary level triggers intracellular calcium mobilization, activating downstream kinase cascades that rapidly stimulate GH granule exocytosis from somatotroph cells. Simultaneously, macimorelin acts at the hypothalamic level to stimulate growth hormone-releasing hormone (GHRH) secretion, which further amplifies the somatotroph response, producing a synergistic GH surge with peak GH concentrations occurring approximately 45–60 minutes post-dose in healthy adults (mean peak GH approximately 31–38 ng/mL at 0.5–1.0 mg/kg; PMID 32325373). In individuals with pituitary or hypothalamic pathology causing AGHD, this secretagogue stimulus produces a blunted GH response, enabling the test to discriminate GH-deficient patients from normal responders. Beyond GH, macimorelin produces modest transient increases in prolactin and free thyroxine, and a minor decrease in TSH, while having no clinically meaningful effect on ACTH, cortisol, LH, FSH, or vasopressin/copeptin levels at the approved diagnostic dose. Body mass index exerts an inverse influence on peak GH response — higher BMI is associated with lower peak GH stimulation — which requires consideration when selecting GH cut-off thresholds, particularly in obese patients (BMI >30 kg/m²; PMID 41793495, 23559086).
Class: Orally active ghrelin receptor agonist (growth hormone secretagogue); synthetic peptidomimetic; GHS-R1a agonist; diagnostic pharmaceutical
Administration & storage
- Storage
- Macrilen granule sachets are stored at room temperature (20–25°C; 68–77°F). Reconstituted solution must be used immediately and not stored. Sachets should be protected from excessive moisture.
- Cautions
- QTc prolongation risk: Macimorelin prolongs the QTc interval (mean ΔΔQTcF 9.61 ms at 4 hours post supratherapeutic 2.0 mg/kg dose; PMID: 32961034). Contraindicated with concomitant medications that prolong QTc interval (class Ia and III antiarrhythmics, fluoroquinolones, etc.). Baseline ECG should be obtained in patients with known cardiac disease or risk factors.,CYP3A4 interactions: Macimorelin is metabolized by CYP3A4. Concomitant CYP3A4 inducers (e.g., rifampin, carbamazepine) may reduce macimorelin plasma exposure and produce falsely low peak GH values, increasing false-positive AGHD diagnoses. CYP3A4 inhibitors may increase macimorelin exposure.,Obesity-related BMI effect: Peak GH response to macimorelin is inversely correlated with BMI. In patients with BMI >30 kg/m², a lower peak GH may occur in non-deficient individuals, increasing the likelihood of false-positive results. The Phase 3 trial excluded BMI >37 kg/m²; test performance in morbid obesity is not established.,Hypothyroidism: Uncontrolled hypothyroidism suppresses GH secretion. Testing should be deferred until thyroid replacement therapy is optimized.,No pediatric approval (as of knowledge cutoff): Macimorelin is approved only in adults. Pediatric safety/PK data exist from a Phase 1/2 dose-escalation study, but no Phase 3 pediatric validation trial results have been published and no pediatric labeling has been approved.
Legal & regulatory status
Macimorelin (Macrilen) received FDA approval on December 20, 2017 (NDA 210557) as an orally administered growth hormone secretagogue indicated for the diagnosis of adult growth hormone deficiency (AGHD). The approved…
Macimorelin is not listed on the WADA Prohibited List as a prohibited substance. It is a prescription-only diagnostic pharmaceutical administered under physician supervision for a single provocation test; it is not…
Macimorelin acetate (Macrilen) is approved in Canada as a diagnostic agent for the assessment of growth hormone deficiency in adults. Canadian authorization follows the clinical data established in the pivotal Phase 3…
What it's studied for
- Diagnosis of adult growth hormone deficiency (AGHD) — Phase 3 validation versus insulin tolerance test Phase III RCT
- Diagnosis of AGHD in adults with Cushing's disease in remission following pituitary surgery or radiation Expert review / mechanistic
- Real-world diagnostic performance and optimal GH cut-off evaluation in clinical endocrinology practice Human observational
- GH stimulation testing in children with suspected growth hormone deficiency — safety and pharmacokinetic evaluation Phase I/II clinical trial
- Diagnosis of adult GHD in older adults and patients with varying BMI — subgroup analyses of diagnostic robustness Phase III post-hoc analysis
- Evaluation as a stimulus for copeptin measurement in the differential diagnosis of diabetes insipidus (investigational; result: negative) Proof-of-concept clinical study
- Structural pharmacology — molecular recognition of macimorelin by the ghrelin receptor for next-generation GHSR agonist design Pre-clinical / structural biology
Safety signals
- QTc interval prolongation
- Drug interactions via CYP3A4 — potential for falsely abnormal GH test results
- Headache — most common drug-related adverse event
- Transient asymptomatic QTc prolongation on ECG — single serious adverse event reported in early validation study
- Obesity (BMI >30 kg/m²) as confounder — increased false-positive AGHD diagnosis rate
- Prolactin elevation — transient pharmacological effect
- Potential for false-positive AGHD diagnosis due to recent food intake or suboptimal fasting
All studies (9)
Frequently asked
How is the macimorelin test different from the insulin tolerance test?
The macimorelin test is taken as an oral drink rather than given intravenously, making it far simpler and safer for patients. The insulin tolerance test (ITT) — traditionally the gold standard — requires IV insulin, close monitoring for dangerous hypoglycemia, and is contraindicated in people with seizure disorders or heart disease. Macimorelin avoids all of those risks. In the pivotal Phase 3 clinical trial, oral macimorelin showed 87–92% sensitivity and 96% specificity versus the ITT as reference standard, with superior test completion rates (99% vs. 82% evaluable after first administration). Published international guidelines and a Delphi consensus of the Growth Hormone Research Society support macimorelin as an accepted alternative to the ITT for adult GHD diagnosis.
Can macimorelin be used in children to test for growth hormone deficiency?
Macimorelin is currently FDA-approved only for adults. A pediatric Phase 1/2 dose-escalation study in 24 children aged 2 to under 18 years found all three tested doses (0.25, 0.5, and 1.0 mg/kg) to be safe and well-tolerated, with no drug-related adverse events reported. The pharmacokinetic and pharmacodynamic profiles were in expected ranges and the authors concluded that 1.0 mg/kg should be carried into a pediatric Phase 3 validation study. However, that Phase 3 pediatric validation has not yet been completed and published, and no pediatric labeling has been issued. Use in children outside of a clinical trial would be off-label.
Does obesity affect the accuracy of the macimorelin test?
Yes, higher body mass index is associated with a blunted growth hormone response to macimorelin — as it is for essentially all GH stimulation tests. In both the Phase 2 validation study and real-world single-center data, patients with obesity (BMI >30–35 kg/m²) showed lower peak GH levels even without confirmed GH deficiency, which can increase false-positive diagnoses. The pivotal Phase 3 trial excluded patients with BMI above 37 kg/m², so test performance in morbid obesity is not well established. Clinicians evaluating obese patients should factor in a higher pre-test probability threshold and consider that the 5.1 ng/mL GH cut-off may be more appropriate than the FDA-approved 2.8 ng/mL cut-off when BMI is elevated.
Are there any heart rhythm concerns with macimorelin?
Yes. Macimorelin prolongs the QTc interval on the ECG. A dedicated thorough QT/QTc study found a mean ΔΔQTcF of approximately 9.6 milliseconds at a supratherapeutic 2.0 mg/kg dose. The prescribing information therefore warns against co-administration with any drugs that independently prolong the QT interval (such as class I and III antiarrhythmics, some fluoroquinolone antibiotics, and certain antipsychotics). Before testing, patients with known heart disease or who are taking QT-prolonging medications should have a baseline ECG, and the prescribing physician should assess the risk-benefit balance. At the approved diagnostic dose (0.5 mg/kg), only one asymptomatic QTc event was reported in early studies.
Can medications interfere with the macimorelin test result?
Several medication categories can invalidate the macimorelin test result. CYP3A4 inducers — such as rifampin or carbamazepine — accelerate breakdown of macimorelin in the body, reducing its plasma levels and blunting the GH stimulus, which can produce a falsely low peak GH and an incorrect diagnosis of GH deficiency. CYP3A4 inhibitors can have the opposite effect. QT-prolonging drugs are a safety contraindication (see cardiac concerns above). Hypothyroidism that is not adequately treated suppresses GH secretion independently of pituitary reserve. Patients should notify their physician of all medications before the test so that appropriate washout periods or test deferrals can be arranged.