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

Abstract

Background:

This phase 1 study investigated the pharmacokinetics (PK) and glucodynamics of insulin lispro (Humalog^®; Eli Lilly and Co., Indianapolis, IN) or regular human insulin (Humulin^® 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/m², 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 90–110 mg/dL: Cohort 1 received 20 U of Humalog ± 300 U of rHuPH20 (11.3 μg/mL), whereas Cohort 2 received 20 U of Humulin R ± 240 U of rHuPH20 (10 μg/mL). Pharmacokinetic parameters included peak serum insulin concentration (C _max), time to C _max (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 t _max by 51% (P = 0.0006) and 58% (P = 0.0002), increased C _max 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 tGIR_max 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.