Interaction between Paracetamol Glucuronide and a Glucose-Sensitive Insulin Molecule (NNC2215): Increased Risk of Hypoglycemia

NNC2215 is an insulin analog with glucose-sensitive properties on activation of the insulin receptor. In NNC2215, a glucoside and a macrocycle with strong affinity to glucose were conjugated to insulin. This introduced a switch that is open (activated) or closed (inactivated) at high or low glucose, respectively. The current study investigated the interaction between NNC2215 and paracetamol glucuronide (PaG), a major human metabolite of paracetamol. Interactions between PaG or d-glucose and NNC2215 were investigated using native mass spectrometry and insulin receptor binding studies in vitro. Interactions between PaG or l-glucose and NNC2215 were studied during glucose clamp conditions in domestic pigs. NNC2215 bound >10-fold stronger to PaG than to d-glucose in vitro. At a clinically relevant PaG concentration (70 μmol/L), the binding affinity of NNC2215 to the insulin receptor was increased, particularly at low glucose concentrations. In the clamp experiment, intravenous administration of 2.0 g PaG versus 0.3 g/kg l-glucose led to a similar glucodynamic effect. These data demonstrate a relevant interaction between PaG and NNC2215, potentially introducing hypoglycemia risk with NNC2215 versus nonglucose-sensitive insulin after paracetamol administration. When engineering a glucose-sensitive insulin, it should be considered whether molecules other than glucose can alter the insulin activity.