Accelerated Pharmacokinetics and Glucodynamics of Prandial Insulins Injected With Recombinant Human Hyaluronidase

Background: This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog (R); Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin (R) R; Eli Lilly and Co.) administered with or without (+/-) recombinant human hyaluronidase (rHuPH20). Methods: Healthy male volunteers (n = 26), 18-55 years old with body mass index 18-28 kg/m(2), weight > 70 kg, and normal fasting glucose, were randomized to a crossover sequence of two subcutaneous injections, each followed by a 6-h euglycemic clamp targeting glucose 90-110mg/dL: Cohort 1 received 20 U of Humalog+/-300U of rHuPH20 (11.3 mu g/mL), whereas Cohort 2 received 20 U of Humulin R+/-240U of rHuPH20 (10 mu g/mL). Pharmacokinetic parameters included peak serum insulin concentration (C-max), time to Cmax (t(max)), and area under the curve (AUC) of serum concentration versus time. Glucodynamic parameters included time to maximal glucose infusion rate (tGIR(max)) and area under the GIR-versus-time curve (G). Results: For Humalog and Humulin R, respectively, rHuPH20 co-administration reduced tmax by 51% (P = 0.0006) and 58% (P = 0.0002), increased Cmax by 90% (P = 0.0003) and 142% (P<0.0001), increased early exposure (AUC(0-2h)) by 85% (P < 0.0001) and 211% (P < 0.0001), and reduced late exposure (AUC(4-6h)) by 41% (P < 0.0001) and 48% (P < 0.0001). Similarly, rHuPH20 reduced tGIRmax by 41% (P = 0.006) and 35% (P = 0.01), increased early metabolism (G(0-2h)) by 52% (P = 0.001) and 127% (P < 0.0001), and reduced late metabolism (G(4-6h)) by 29% (P = 0.002) and 26% (P = 0.03) for Humalog and Humulin R, respectively. Injections were well tolerated. Conclusions: Co-administration of rHuPH20 accelerated the PK and glucodynamics of both insulin formulations. Additional studies are necessary to evaluate the clinical relevance of these findings in patients with diabetes.