Fluctuation and reproducibility of exposure and effect of insulin glargine in healthy subjects

Aim: Low diurnal fluctuation and high day-to-day reproducibility in exposure and effect characterize beneficial basal insulin products. Two insulin glargine (LANTUS) formulations [without (R) or with polysorbate-20 (T)], added to minimize unfolding of proteins and subsequent formation of fibril structures, were assessed for equivalence in exposure and effect, and aspects of fluctuation and reproducibility in time-concentration and time-action profiles. Methods: A dose of 0.4 U/kg was subcutaneously administered to 24 healthy subjects in a two-sequence (R-T-R-T or T-R-T-R), randomized, four-way crossover trial utilizing 30-h Biostator-based euglycaemic glucose clamps. Results: Identical serum insulin glargine concentration and time-action profiles established average, individual and population equivalence in insulin exposure and effect. Point estimates for 24-h area under the curve for insulin (INS AUC(0-24) (h)) and glucose infusion rates (GIR-AUC(0-24) (h)) were 97% [90% confidence interval (CI): 91-103%] and 100% (88-114%), respectively. Within- subject variability (coefficient of variation) for INS-AUC(0-24) (h) and GIR-AUC(0-24) (h) were 19% ( 95% CI: 14-25%) and 34% (24-43%), respectively. The diurnal relative fluctuation of the serum insulin glargine concentration was 20% (95% CI: 19-21%). Conclusion: Insulin glargine in either formulation presents with a high day-to-day reproducibility of a uniform release after injection enabling an effective basal insulin supplementation.