Insulin Degludec/Aspart (IDegAsp) Premix Exhibits Additive Pharmacokinetics and Dynamics in Canine Model

Diabetes mellitus is a globally prevalent metabolic disorder requiring insulin therapy, often involving complex regimens. Premixed insulins offer the convenience of combined basal and prandial glucose control, but their nonclinical validation, particularly regarding component interactions and species translation, has been limited. Understanding how individual insulin analogs behave when co-formulated is crucial for optimizing therapeutic efficacy and safety. This study addresses the gap in systematic nonclinical data for premixed insulins, specifically evaluating the interaction of insulin degludec (IDeg) and insulin aspart (IAsp) in a combined formulation.

Researchers employed a Beagle dog euglycemic clamp model to assess insulin formulations. Twelve dogs received 0.75 IU/kg subcutaneous (SC) doses of insulin degludec (IDeg), insulin aspart (IAsp), and their 70/30 premixed formulation (IDegAsp). The study used a randomized, single-dose, three-period crossover design with 7-day washouts between treatments. Blood glucose was clamped at 5.0 mmol/L for 24 hours, while monitoring glucose infusion rate (GIR), plasma insulin, and serum C-peptide levels. Drug concentrations were quantified using LC-MS/MS, and component interactions were assessed via Sigmoid-Emax and Loewe models.

The euglycemic clamp successfully maintained stable blood glucose across all treatment groups, with no instances of clinical hypoglycemia observed. Co-formulation of IDeg and IAsp induced only modest shifts in the time to maximum plasma concentration (Tmax). > Dose-normalized exposures were comparable between single and combined formulations, with relative bioavailability remaining below 110%, indicating minimal impact on absorption. Elimination parameters for both insulins remained unchanged when co-formulated, supporting independent clearance pathways for each component. IDeg consistently exerted long-acting glucose-lowering effects, while IAsp demonstrated rapid onset and short duration, with IDegAsp integrating both dual characteristics. The C-peptide curve for IDeg closely resembled that of IDegAsp, further suggesting independent action. Glucose infusion rate profiles for IAsp and IDegAsp were similar despite morphological differences in their concentration curves. Both Sigmoid-Emax and Loewe models confirmed additive rather than synergistic interactions between IDeg and IAsp.