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; 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/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 90-110 mg/dL: Cohort 1 received 20 U of Humalog +/- 300 U of rHuPH20 (11.3 microg/mL), whereas Cohort 2 received 20 U of Humulin R +/- 240 U of rHuPH20 (10 microg/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.
Vaughn
Daniel E
DE
Halozyme Therapeutics, Inc., San Diego, California 92121, USA. dvaughn@halozyme.com
Yocum
Richard C
RC
Muchmore
Douglas B
DB
Sugarman
Barry J
BJ
Vick
Andrew M
AM
Bilinsky
Igor P
IP
Frost
Gregory I
GI
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology; D061268:Insulin Lispro; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D055815:Young Adult
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro; D011994:Recombinant Proteins; D006821:Hyaluronoglucosaminidase