How cyclodextrin modification dictates bone affinity: Insights from the bone toxicity evaluation of adamgammadex

Drug-induced bone toxicity represents an important safety concern, particularly in pediatric populations where bone development is currently at a critical juncture and highly sensitive to pharmacological interference. Adamgammadex is a novel modified γ-cyclodextrin designed for rapid neuromuscular blockade reversal drug nearing market approval. In this study, we investigated the potential bone toxicity of adamgammadex in both juvenile and adult rats. Pharmacokinetic studies revealed that adamgammadex (30 mg/kg injection) is distributed in the bones and teeth of rats. It has a fast metabolic rate with no difference between males and females. However, in juvenile rats, the retention percentage is higher than in adults, and the elimination time is longer. Long-term administration of adamgammadex in rats for 4 weeks (200, 600, and 2000 mg/kg, daily) or 9 weeks (30, 150, and 450 mg/kg, weekly) from juveniles to adults stage, no significant toxic effects on bones, teeth, or bone-related blood biomarkers were detected. Similarly, administration of adamgammadex (150, 450, and 1500 mg/kg, daily) to beagle dogs for 4 weeks revealed no notable changes in serum bone-related biomarkers. In vitro studies have shown that natural α, β and γ-cyclodextrin hardly bind to hydroxyapatite, but modification of the ring-exterior chain affects the binding affinity of the cyclodextrins to hydroxyapatite. However, the newly introduced N-acetyl-L-cysteine moiety in adamgammadex only slightly increases this binding affinity.