Recombinant activated factor VIIa (rFVIIa) is a well-established treatment for bleeding episodes in patients with congenital or acquired haemophilia A or B with inhibitors to factors VIII and IX and patients with FVII deficiency. The aim of this trial was to demonstrate bioequivalence between the currently marketed (rFVIIa/NovoSeven) and a new rFVIIa formulation (VII25) stable at up to 25 degrees C. Furthermore, short-term safety and tolerability of VII25 and pharmacokinetics of both formulations were investigated. In this single-centre, randomized, double-blind, two-way cross-over trial, healthy male subjects received one intravenous bolus injection of rFVIIa and one of VII25, both at 90 microg kg(-1), in a randomized order 2-3 weeks apart. Mean VII25/rFVIIa ratio for area under the plasma activity-time curve from time 0 to last quantifiable activity (primary bioequivalence endpoint), was 0.93, 90% confidence interval (CI) (0.89-0.96), within the predefined bioequivalence range (0.80-1.25). Secondary pharmacokinetic parameters were comparable between formulations. No serious adverse events were observed. Six mild or moderate treatment-emergent adverse events were reported in five subjects. Coagulation-related parameter profiles were similar between rFVIIa and VII25. No clinically abnormal changes were observed for laboratory parameters and no subjects developed FVIIa antibodies. This trial demonstrated bioequivalence between the currently available rFVIIa and VII25 stable at up to 25 degrees C. VII25's 'user-friendly' formulation removes the inconvenience of storing/transporting at 2-8 degrees C, and as the drug substance is the same, the activity and safety established for rFVIIa is maintained.
NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist.Binding of 35S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of 35 S-MK677. However, the observed K i value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells.The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155 Ϯ 23 nmol/kg and 91 Ϯ 7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown.The effect of NN703 on GH release after i.v. and oral dosing in beagle dogs was studied. NN703 dosedependently increased the GH release after oral administration. At the highest dose (20 mmol/kg), a 35-fold increase in peak GH concentration was observed (49.5 Ϯ 17.8 ng/ml, mean Ϯ S.E.M.). After a single i.v. dose of 1 mmol/kg the peak GH plasma concentration was elevated to 38.5 Ϯ 19.6 ng/ml (mean Ϯ S.E.M.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1 Ϯ 0.4 h.A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 mmol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group.In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.