Non-clinical studies indicating lack of interactions between iron/calcium ions and linzagolix, an orally available GnRH antagonist

Abstract

1. Linzagolix is an orally available gonadotropin-releasing hormone antagonist used to treat sex-hormone-dependent diseases in women. This study aimed to investigate drug-drug interactions between linzagolix and iron/calcium ions in the intended clinical setting by conducting pharmacokinetic studies in vitro and in rats.

2. Insoluble precipitate formation with metal ions was evaluated by measuring linzagolix concentrations in four types of bio-relevant dissolution media (fasted/fed state simulated gastric fluid and fasted/fed state simulated gastric fluid version 2), and chelate complex formation with metal ions was evaluated by release of linzagolix from a cellulose membrane sac. In these in vitro studies, linzagolix showed no potential for insoluble precipitate formation under fasted/fed conditions and no chelate complex formation in the presence of metal ions.

3. In rats, the plasma concentration-time profiles of linzagolix and iron ion were similar regardless of whether they were administered with or without ferrous sulphate and linzagolix choline at clinically relevant doses. Thus, linzagolix and iron ion had no effect on each other’s absorption in vivo.

4. In conclusion, linzagolix is unlikely to cause clinically relevant drug-drug interactions by chelating metal ions according to the results of in vitro and in vivo studies.

Keywords:

• Linzagolix
• GnRH antagonist
• ADME
• DDI
• iron ion
• calcium ion

Acknowledgements

The authors thank all members of Kissei pharmaceutical Co., Ltd. who assisted with the pre-clinical studies of linzagolix.

Disclosure statement

The authors are employees of Kissei Pharmaceutical Co., Ltd.