Inside the body with Ipamorelin

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]

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]

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]

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]

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]

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]