Ipamorelin

1. 01Brain

   It presses the ghrelin receptor

   Ipamorelin acts like ghrelin, the hormone that tells you that you are hungry, even though its building blocks are different. It fits into the same lock on cells, called the ghrelin receptor. Most of what we know about this step comes from lab cells and animals.

   For experts

   Antagonist profiling (Raun 1998) showed that ipamorelin, like GHRP-6, stimulates GH release through a GHRP-like receptor, the receptor now known as the ghrelin receptor (GHSR-1a); FDA staff describe the main site of action as ghrelin receptors on GHRH-positive hypothalamic neurons. GHSR-1a is a G protein-coupled receptor that signals mainly through Gq/11 and phospholipase C. The receptor is also found in peripheral tissues such as stomach, intestine, pancreas and fat. Receptor binding data for ipamorelin in humans were not found; the receptor pharmacology comes from animal and cell work.[src][src]

2. 02Brain

   The pituitary releases growth hormone

   The pituitary is a pea-sized gland under the brain. When the receptor is switched on, it lets out a burst of growth hormone. In pigs, it did this without also raising the stress hormone cortisol, and a study in healthy men showed the same growth hormone burst.

   For experts

   In rats, ipamorelin released GH from primary pituitary cells with potency similar to GHRP-6 (EC50 1.3 nmol/L). In conscious swine it released GH with an ED50 of 2.3 nmol/kg and did not raise FSH, LH, prolactin or TSH; unlike GHRP-2 and GHRP-6 it did not raise ACTH or cortisol above the level seen with GHRH, even at doses over 200 times the GH ED50. In healthy men, intravenous ipamorelin produced a single episode of GH release at every dose that produced a measurable response. The selectivity data are from swine, not from humans.[src][src]

3. 03Bloodstream

   The signal is short

   After ipamorelin goes into the blood, the growth hormone burst is quick. In healthy men it peaked in under an hour and was almost gone by six hours. The body clears half of the peptide in about two hours, and in rats much of it leaves in urine.

   For experts

   In healthy men, ipamorelin followed linear two-compartment kinetics with a terminal half-life of about 2 h. GH peaked at about 0.67 h and returned to very low concentrations by about 6 h at all doses; the modelling suggests that longer exposure does not necessarily keep stimulating GH release. In rats, plasma half-life after an intravenous injection was about 27 minutes, clearance was about 5-fold lower than for GHRP-6, and 60-80% was recovered as intact peptide, mainly in urine. Pharmacokinetics for subcutaneous or other routes in humans were not identified by FDA.[src][src][src]

4. 04Liver

   Growth hormone can nudge the liver to make IGF-1

   Growth hormone normally tells the liver to make another hormone, IGF-1. US FDA staff worry that, because ipamorelin raises growth hormone, it could bring the same risks as growth hormone medicines. For ipamorelin, this step is expected but has not been shown in humans. In rats it did not change IGF-1 levels.

   For experts

   FDA staff note that growth hormone secretagogues stimulate endogenous GH, which in turn stimulates IGF-1, and that approved recombinant GH labels list class risks (neoplasm, glucose intolerance and diabetes, intracranial hypertension, fluid retention, hypoadrenalism, hypothyroidism, pancreatitis); they were concerned similar risks could apply. FDA also cites QT prolongation with the approved secretagogue macimorelin. No human IGF-1 data for ipamorelin were identified. In adult female rats, 15 days of ipamorelin did not change total IGF-I or IGFBPs, and the pituitary GH response to a repeat challenge was marginally reduced.[src][src]

5. 05Bone

   Bones grew in rat studies (animals only)

   In young adult female rats, ipamorelin made bones grow a bit longer and gave them a bit more mineral overall. This was only in animals. It has not been shown to work this way in people.

   For experts

   Animal-only evidence. In adult female rats, ipamorelin dose-dependently increased the longitudinal growth rate of the tibia (from 42 to 52 micrometres/day at the highest dose tested) and body weight gain over 15 days. In a 12-week rat study, ipamorelin increased total bone mineral content measured by DXA, but this reflected larger bones (greater cross-sectional area) with unchanged volumetric bone mineral density, and BMC corrected for body weight was unchanged. No human bone data were found.[src][src]

6. 06Gut

   It may speed up the gut in rats, but not clearly in patients

   Ghrelin also helps the stomach and gut move food along. In rats after belly surgery, ipamorelin got the gut going sooner. In a trial of patients after bowel surgery, it did not clearly help.

   For experts

   In a rat model of postoperative ileus (animal-only), a single intravenous dose shortened time to first bowel movement, and repeated dosing increased fecal output, food intake and weight gain. In the human phase 2 trial after bowel resection (117 enrolled), median time to first tolerated meal was 25.3 h with ipamorelin versus 32.6 h with placebo (p = 0.15), and no key or secondary efficacy endpoint differed significantly. FDA staff also highlighted that fatal serious adverse events occurred in the ipamorelin arm (after surgical complications), though causality was unclear.[src][src][src]

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