Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase

Abstract

Objective: To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20).

Research design and methods: This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.15 units/kg) with or without rHuPH20.

Results: The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123-131 min and 50% total glucose infused at 183-186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71-79 min and 50% glucose infused at 127-140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action.

Conclusions: Coinjection of rHuPH20 with rapid-acting analogs accelerated insulin exposure, producing an ultra-rapid time-action profile with a faster onset and shorter duration of insulin action.

Trial registration: ClinicalTrials.gov NCT00979875.

Figures

Figure 1

Cumulative exposure and action of insulins glulisine, lispro, and aspart after subcutaneous injection with and without rHuPH20. Blood samples were collected on each dosing day at 30, 20, and 10 min before and 3, 6, 9, 12, 15, 20, 25, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 min after injection of each study drug for the measurement of serum insulin samples using a conventional competitive radioimmunoassay (Millipore, St. Charles, MO) using broad-spectrum antiserum (catalog 1013-K; Millipore) that binds each of the analogs and human insulin and was validated for each of the analogs individually. A Biostator was used to clamp blood glucose at 90% fasting level to suppress endogenous insulin production with tight blood glucose control (individual clamp glucose SDs were between 3.5 and 6.8 mg/dL). Results are displayed as a cumulative percent of the total exposure (left panel; see text for total exposure) and total glucose infused (right panel; mean ± SD total glucose infused were 1.7 ± 0.6, 1.7 ± 0.6, 1.8 ± 0.5, 1.7 ± 0.5, 1.9 ± 0.5, and 1.4 ± 0.5 for glulisine, glulisine plus rHuPH20, lispro, lispro plus rHuPH20, aspart, and aspart plus rHuPH20, respectively).