Ipamorelin 10 mg

Ipamorelin is a synthetic pentapeptide with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 (free peptide: CAS 170851-70-4, C38H49N9O5, 711.87 g/mol). It does not occur in nature. The molecule originated in a Novo Nordisk peptide programme under the development code NNC 26-0161 and was first characterised in the peer-reviewed literature by Raun and colleagues in 1998, who report that it was identified within a series of compounds lacking the central Ala-Trp dipeptide of growth hormone releasing peptide-1. The phase 2 postoperative-ileus trial was sponsored by Helsinn Therapeutics (U.S.), Inc.; a separate human pharmacokinetic study was published in 1999.

Four features define its chemistry. The N-terminal residue is Aib (2-aminoisobutyric acid), an achiral, alpha,alpha-disubstituted amino acid not used in ribosomal protein synthesis. Positions three and four are D-amino acids: D-3-(2-naphthyl)alanine, a bulky bicyclic aromatic residue, and D-phenylalanine. The C-terminus is a carboxamide rather than a free acid. D-configuration residues, alpha,alpha-disubstitution at the N-terminus and C-terminal amidation are the standard medicinal-chemistry modifications used to build peptides that resist the amino- and carboxypeptidases acting on ordinary L-peptides; PowerfullyPeptides makes no measured stability claim for this material beyond the storage conditions stated on the specification. The only standard residues are L-histidine and L-lysine, whose imidazole and epsilon-amino groups give the molecule its basic character.

Structurally, ipamorelin sits apart from the two other families of compounds studied on the growth hormone axis. Ghrelin, the endogenous ligand of the GHS-R1a receptor, is a 28-residue peptide that requires an n-octanoyl group on Ser3 for receptor activity. GHRH is a 44-residue peptide and its common analogues run to 29 residues. Ipamorelin carries no lipid modification, no cysteine and therefore no disulfide bridge, and at roughly 712 Da it is a fraction of the mass of either. It is produced by solid-phase peptide synthesis, purified by reversed-phase HPLC and isolated by lyophilisation as the acetate salt. Because the supplied material is the acetate salt rather than the free peptide, and because residual acetate counterions and bound water are part of the dried powder, gross vial mass and net peptide mass are not identical; the free peptide has a formula mass of 711.87 g/mol against 771.9 g/mol for the monoacetate. This material is supplied at >=99% purity by HPLC.

The defining pharmacology paper is Raun et al. (1998). In primary rat pituitary cells the authors reported an EC50 of 1.3 +/- 0.4 nmol/L with 85 +/- 5% of maximal efficacy, against 2.2 +/- 0.3 nmol/L and 100% efficacy for GHRP-6. In pentobarbital-anaesthetised rats the reported ED50 was 80 +/- 42 nmol/kg, producing 1545 +/- 250 ng GH/mL, versus 115 +/- 36 nmol/kg and 1167 +/- 120 ng GH/mL for GHRP-6. In conscious swine the reported ED50 was 2.3 +/- 0.03 nmol/kg yielding 65 +/- 0.2 ng GH/mL of plasma, against 3.9 +/- 1.4 nmol/kg and 74 +/- 7 ng GH/mL for GHRP-6. Specificity was studied in swine: the authors report that none of the secretagogues tested affected FSH, LH, prolactin or TSH plasma levels, that GHRP-6 and GHRP-2 both raised plasma ACTH and cortisol, and that ipamorelin did not release ACTH or cortisol at levels significantly different from those observed following GHRH stimulation, an absence of difference that persisted at doses more than 200-fold above the ED50 for GH release. That comparison between compounds, not any outcome, is what the paper is cited for.

Two rodent skeletal studies followed. Johansen et al. (1999) gave adult female rats 0, 18, 90 or 450 micrograms daily by subcutaneous injection in three divided doses for 15 days. Longitudinal bone growth rate measured 42 micrometres/day in the vehicle group against 44, 50 and 52 micrometres/day in the three dose groups (P<0.0001), alongside dose-dependent body weight gain. The same study found no significant effect on total IGF-I, IGF binding proteins, or serum markers of bone formation and resorption, and reported a marginally reduced plasma GH response to ipamorelin after the treatment period (P<0.03) with an unchanged response to GHRH. Svensson et al. (2000) infused 0.5 mg/kg/day of ipamorelin continuously for 12 weeks in adult female rats, alongside GHRP-6 at 0.5 mg/kg/day. Body weight and total tibial and vertebral bone mineral content measured by DXA rose relative to vehicle-treated controls, but the increase disappeared once corrected for body weight change, and volumetric bone mineral density was unchanged; the authors attributed the change to increased bone growth and bone dimensions rather than increased density.

Human pharmacokinetic data come from a single published study. Gobburu et al. (1999) used a dose-escalation design with five 15-minute infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg) and eight healthy male subjects at each dose level. They reported that the pharmacokinetic parameters showed dose-proportionality, with a terminal half-life of approximately 2 hours, clearance of 0.078 L/h/kg and a volume of distribution of 0.22 L/kg. Growth hormone response was fitted with an indirect response model giving an SC50 for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mIU/L/h. The authors noted that inter-individual variability in the pharmacodynamic parameters was larger than that of the pharmacokinetic parameters.

A separate line of work examined gastrointestinal motility rather than the growth hormone axis. Greenwood-Van Meerveld et al. (2012) used a rat model of postoperative ileus induced by abdominal surgery, administering ipamorelin at 0.014 to 0.14 micromol/kg intravenously. Surgery delayed gastric emptying, leaving 78 +/- 5% of the meal in the stomach in vehicle-treated animals against 44 +/- 6% in non-surgical controls. At 0.014 micromol/kg, 52 +/- 11% of the meal remained (P<0.05 versus vehicle). In isolated gastric fundus preparations, ipamorelin at 1 micromolar reversed the surgery-induced inhibition of contraction. The authors attributed the effect to ghrelin-receptor-mediated activation of cholinergic excitatory neurons.

That preclinical work led to the only published controlled trial. Beck et al. (2014) ran a phase 2, randomised, double-blind, placebo-controlled proof-of-concept study (NCT00672074, sponsored by Helsinn Therapeutics (U.S.), Inc.) in bowel resection patients: 117 patients enrolled, of whom 114 composed the safety and modified intent-to-treat populations, receiving intravenous infusions of 0.03 mg/kg twice daily on postoperative day 1 to 7 or hospital discharge. Median time to first tolerated meal was 25.3 hours on ipamorelin against 32.6 hours on placebo, p = 0.15. Adverse events occurred in 87.5% of the ipamorelin group and 94.8% of the placebo group. The authors concluded that the regimen was well tolerated and that there were no significant differences between ipamorelin and placebo in the key and secondary efficacy analyses. The trial completed in December 2009. Ipamorelin holds no marketing authorisation in Europe or the US. The published record overall is modest: a small cluster of rodent endocrinology and gastrointestinal motility studies from the late 1990s and 2000s, one human pharmacokinetic study, and one phase 2 trial that missed its endpoint. There is no long-term human safety dataset.