Intra-Subject Variability in Pharmacokinetics and Pharmacodynamics of Basal Insulin at Two Single-Dose Levels: Findings from Euglycemic Glucose Clamp Bioequivalence Studies of Insulin Degludec.

Background/Objectives: Standard protocols for euglycemic clamp studies involving long-acting insulin formulations typically recommend a dosage range of 0.4~0.6 U/kg for a single dose. This investigation aimed to evaluate the bioequivalence of an insulin degludec (IDeg) biosimilar versus its reference product, while simultaneously analyzing intra-subject variability in pharmacokinetic (PK) and pharmacodynamic (PD) metrics at doses of 0.4 U/kg and 0.5 U/kg in healthy Chinese adults. Methods: This randomized, single-dose, crossover euglycemic clamp study involved 52 participants who received either 0.4 U/kg (Group A, n = 26) or 0.5 U/kg (Group B, n = 26) of both formulations. Key outcomes measured included AUCIDeg,0-24h, Cmax,IDeg, and AUCGIR,0-24h. Secondary endpoints encompassed AUC of IDeg or GIR at specified intervals and time-related metrics. Intra-subject variability (intra-CV) was assessed for PK/PD parameters. Results: All subjects completed the study without dropping out. Baseline demographics showed no significant disparities between groups. Bioequivalence criteria were satisfied for all PK/PD endpoints, with 90% confidence intervals (CIs) falling within the 0.80~1.25 range, with the exception of AUCGIR,0-12h at the 0.4 U/kg dose (90% CI: 0.944~1.333). Notably, the 0.4 U/kg dose exhibited significantly higher intra-CV for AUCGIR,0-24h (24.9% vs. 20.2%, p = 0.049) and AUCGIR,0-12h (37.6% vs. 27.6%, p = 0.005) compared to the 0.5 U/kg dose. Conclusions: Applying a 0.5 U/kg dose reduced intra-subject PD variability and improved equivalence likelihood for secondary endpoints, indicating that a higher single dose might be optimal in bioequivalence study design.