Reduction in Intrasubject Variability in the Pharmacokinetic Response to Insulin After Subcutaneous Co-Administration with Recombinant Human Hyaluronidase in Healthy Volunteers

Background: This study was designed to test the hypothesis that co-administration of recombinant human hyaluronidase (rHuPH20) with regular insulin or insulin lispro will reduce intrasubject variability in pharmacokinetic end points compared with lispro alone. Methods: Healthy adult volunteers (18-55 years old) were enrolled in this phase 1, randomized, double-blind, crossover study. Subjects were administered two injections, each on a separate occasion, of three treatments during six euglycemic clamps. Treatments were 0.15 U/kg insulin lispro, 0.15 U/kg insulin lispro with 5 mu g/mL rHuPH20, and 0.15 IU/kg regular insulin with 5 mu g/mL rHuPH20. Insulin formulations were administered at a concentration of 40U/mL. Serum immunoreactive insulin levels, blood glucose concentration, and glucose infusion rate determinations were made at baseline and for approximately 8 h after study drug administration. Intrasubject variability was assessed using a general linear mixed model with a fixed effect for treatment using a compound symmetric covariance matrix. Results: Co-injection of rHuPH20 with lispro significantly reduced intrasubject root mean square differences in time to peak serum insulin, time to early 50% peak serum insulin (t(50%)), and time to late t(50%) levels compared with lispro alone. Also, the intrasubject coefficient of variation for percentage of total area under the plasma concentration-versus-time curve for early time intervals compared with lispro alone was reduced. Intrasubject variability for regular insulin with rHuPH20 for most pharmacokinetic parameters was similar to the variability of lispro alone, although variability in early exposure was significantly reduced. Conclusions: Co-administration of rHuPH20 with lispro significantly reduced the variability of insulin pharmacokinetics relative to insulin lispro alone.