Degarelix, a novel GnRH antagonist, causes minimal histamine release compared with cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.
OBJECTIVE
Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.


METHODS
Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 µg ml(-1) for all, except for ganirelix 1, 10 or 100 µg ml(-1) ). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80.


RESULTS
Degarelix had no significant effect on basal histamine release in the 3 to 300 µg ml(-1) concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 ± 27% at the 100 µg ml(-1) concentration. At 30 and 300 µg ml(-1) concentrations abarelix (143 ± 29% and 362 ± 58%, respectively, P < 0.05) and cetrorelix (228 ± 111% and 279 ± 46%, respectively, P < 0.05) caused significantly increased histamine release.


CONCLUSIONS
In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings.
Koechling
Wolfgang
W
Ferring Pharmaceuticals A/S, Copenhagen, Denmark. wolfgang.koechling@ferring.com
Hjortkjaer
Rolf
R
Tankó
László B
LB
D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006632:Histamine / Q000032:analysis*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*
D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone; D006632:Histamine; C061018:ganirelix; C062876:cetrorelix; C423508:abarelix