Chemical formula: C₂₆H₃₀N₆O₃ Molecular mass: 474.565 g/mol
Macimorelin is an orally available peptidomimetic with growth hormone (GH) secretagogue activity similar to ghrelin. Macimorelin stimulates GH release by activating growth hormone secretagogue receptors (GHSR) present in the pituitary and hypothalamus.
In dose finding studies in healthy subjects, maximum stimulation of GH secretion was achieved following single dose administration of 0.5 mg/kg macimorelin. Maximum GH levels have been observed approximately 45 to 60 minutes after administration of macimorelin. In a diagnostic study comparing macimorelin with the insulin tolerance test (ITT) stimulated GH concentrations after macimorelin were on average 1.4 fold higher than in the ITT.
The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg, i.e., 4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 ms (11.4 ms) at 4 h post-dose, which occurred after the mean maximum macimorelin plasma concentration (0.5 h).
A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively)). All three dose levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown.
Macimorelin was absorbed rapidly and the maximum plasma macimorelin concentrations (Cmax) were observed approximately 30 minutes to 1 hour and 10 minutes after oral administration of 0.5 mg/kg macimorelin after fasting for at least 8 hours. A liquid meal decreased the macimorelin Cmax and AUC by 0.42 and 0.5 fold, respectively.
The oral bioavailability may be limited (among others) by first pass metabolism via CYP3A4.
Macimorelin is moderately bound to plasma proteins. Plasma protein binding decreases with increasing concentrations from 78% at 0.1 µM to 62% at 10 µM. At the clinically relevant concentration of 0.1 µM (clinical Cmax = 11.2 ng/ml = approx. 0.02 µM), the unbound fraction of macimorelin in human plasma is 22%.
CYP3A4 is the major enzyme to metabolize macimorelin. Studies to detect macimorelin metabolites did not identify any metabolites.
An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin.
Macimorelin was eliminated with a mean terminal half-life (T1/2) of 4.1 hours.
Macimorelin showed a dose-dependent release of GH after oral dosing. A dose of 0.5 mg/kg macimorelin was shown to induce maximal GH release. Maximal GH release has been observed at macimorelin plasma concentrations of ≥7 ng/mL.
No studies have been conducted to evaluate the pharmacokinetics of macimorelin in paediatric patients or in patients with renal or hepatic impairment. Only limited pharmacokinetic data are available in the elderly.
Preclinical data from safety pharmacology, repeated dose toxicity and genotoxicity studies reveal no specific hazard for humans. No studies to assess carcinogenicity and effects on reproduction and development have been conducted.
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