Bioavailability and variability of biphasic insulin mixtures.

Absorption of subcutaneously administered insulin is associated with considerable variability. Some of this variability was quantitatively explained for both soluble insulin and insulin suspensions in a recent contribution to this journal (Søeborg et al., 2009). In the present article, the absorption kinetics for mixtures of insulins is described. This requires that the bioavailability of the different insulins is considered. A short review of insulin bioavailability and a description of the subcutaneous depot thus precede the presentation of possible mechanisms associated with subcutaneous insulin degradation. Soluble insulins are assumed to be degraded enzymatically in the subcutaneous tissue. Suspended insulin crystals form condensed heaps that are assumed to be degraded from their surface by invading macrophages. It is demonstrated how the shape of the heaps affects the absorption kinetics. Variations in heap formation thus explain some of the additional variability associated with suspended insulins (e.g. NPH insulins) compared to soluble insulins. The heap model also describes how increasing concentrations of suspended insulins lead to decreasing bioavailability and lower values of Cmax. Together, the findings constitute a comprehensive, quantitative description of insulin absorption after subcutaneous administration. The model considers different concentrations and doses of soluble insulin, including rapid acting insulin analogues, insulin suspensions and biphasic insulin mixtures. The results can be used in both the development of novel insulin products and in the planning of the treatment of insulin dependent diabetic patients.