Pharmacokinetics and Pharmacodynamics of Biosimilar Insulins: Is Clamp Technology Fit for Purpose?

The euglycemic glucose clamp was first used to assess the new human insulins in the early 1980s by comparing pharmacodynamics (PD) of square-wave intravenous infusions in terms of the clamp glucose infusion rate (1). Shortly afterward, the technique was adapted to study the profile of action of subcutaneously injected insulin (2) and in people with type 1 diabetes rather than people without diabetes. One major advantage of the clamp is that it allows the study at the same time of both the pharmacokinetics (PK), the plasma concentration absorption profile of injected insulin, and PD in terms of measures such as onset, peak, peak:trough ratio, duration, and area under the curve (Table 1). Attractively, the time-action profiles can be visualized. Although initially used for mealtime insulins, the technique was soon applied to extended-acting insulins, comparing insulin-action profiles of nominally similar insulins (NPH preparations) from different manufacturers (3). View this table: Table 1 Some glucose clamp advantages and limitations in the study of subcutaneous injection profiles of insulin preparations Mealtime insulins can be compared, to a useful extent, in people with type 1 diabetes (C-peptide negative) using standardized or usual meals on a background of steady-state basal insulin or infusion (4). Such an option is not available for long-acting insulins, so glucose clamp studies are particularly important for assessing and comparing these. Thus, while general guidelines for comparing a biosimilar medication (a copy) with the original product emphasize PK/PD studies (5,6), specific guidelines for insulin as drawn up by the European regulators go into considerable detail on glucose clamp studies (7). In …