Ipamorelin

In a multicentre, double-blind, placebo-controlled phase 2 trial in 114 adults after small or large bowel resection, median time from first dose to tolerating a standardised solid meal was 25.3 hours with ipamorelin versus 32.6 hours with placebo, which did not reach statistical significance (p = 0.15). No secondary efficacy endpoint separated from placebo.³

In growth-hormone-deficient lit/lit mice and GH-intact littermates, ipamorelin raised body weight by about 15% at two weeks and increased fat pad weight relative to body weight in both genotypes, whereas growth hormone itself reduced relative fat mass in lit/lit mice, so the adiposity effect does not require GH. Serum leptin and food intake rose in GH-intact mice.⁹

In rats made catabolic with prednisolone 4 mg/kg/day for seven days, ipamorelin 0.5 mg/kg/day reduced the hepatic capacity of urea-nitrogen synthesis by 20% (p < 0.05) and neutralised whole-body nitrogen balance, against a 33% reduction and a 2.5-fold improvement in nitrogen balance in the growth hormone 1 mg/kg/day arm: the same direction of effect as GH, less efficiently at the doses compared.¹³

In ferrets given cisplatin, ipamorelin reduced cisplatin-induced weight loss during the delayed phase (48 to 72 hours) by approximately 24% versus vehicle but had no effect on acute or delayed emesis; in isolated ferret ileum it inhibited electrical-field-stimulation-induced contractions by 54.4% (IC50 11.7 micromolar), versus 94.4% for anamorelin.²

In rats subjected to laparotomy and intestinal manipulation, 78% plus or minus 5% of a technetium-99m-labelled meal still remained in the stomach 15 minutes after gavage in vehicle controls, versus 52% plus or minus 11% after intravenous ipamorelin (p < 0.05), approaching the 44% plus or minus 6% seen in non-surgical controls.⁸

In 40 healthy men given five ascending intravenous infusion rates, ipamorelin showed dose-proportional pharmacokinetics: terminal half-life 2 hours, clearance 0.078 L/h/kg, steady-state volume of distribution 0.22 L/kg. It produced a single episode of growth hormone release peaking at 0.67 hours and declining to negligible concentrations at every dose level; half-maximal GH stimulation occurred at 214 nmol/L.¹¹

In conscious swine, ipamorelin released growth hormone with an ED50 of 2.3 nmol/kg and a maximum of 65 ng GH/mL plasma, closely matching GHRP-6 (ED50 3.9 nmol/kg, maximum 74 ng/mL), yet unlike GHRP-6 and GHRP-2 it did not raise plasma ACTH or cortisol above the levels seen after GHRH stimulation, even at doses more than 200-fold above its own ED50 for GH release.¹

In adult female rats over 15 days, longitudinal bone growth rate at the proximal tibial metaphysis rose dose-dependently from 42 micrometres/day in the vehicle group to 44, 50 and 52 micrometres/day in the 18, 90 and 450 microgram/day groups (p < 0.0001), with a parallel gain in body weight but no change in total IGF-I, IGF binding proteins or serum bone turnover markers.¹⁰

In 8-month-old female rats given methylprednisolone 9 mg/kg/day for three months, animals that also received ipamorelin showed a four-fold higher periosteal bone formation rate and significantly greater maximum tetanic tension of the calf muscles than rats given the glucocorticoid alone.¹⁴

In female Sprague-Dawley rats infused continuously for 12 weeks, ipamorelin increased total tibial and vertebral bone mineral content on DXA relative to vehicle, but the gain tracked body weight: the bone mineral content to body weight ratio and volumetric bone mineral density were unchanged, and peripheral quantitative CT attributed the extra cortical mineral to larger cross-sectional bone area, not denser bone.¹⁵