A recombinant human enzyme for enhanced interstitial transport of therapeutics.
Subcutaneously injected therapeutics must pass through the interstitial matrix of the skin in order to reach their intended targets. This complex, three-dimensional structure limits the type and quantity of drugs that can be administered by local injection. Here we found that depolymerization of the viscoelastic component of the interstitial matrix in animal models with a highly purified recombinant human hyaluronidase enzyme (rHuPH20) increased the dispersion of locally injected drugs, across a broad range of molecular weights without tissue distortion. rHuPH20 increased infusion rates and the pattern and extent of appearance of locally injected drugs in systemic blood. In particular, rHuPH20 changed the pharmacokinetic profiles and significantly augmented the absolute bioavailability of locally injected large protein therapeutics. Importantly, within 24 h of injection, the interstitial viscoelastic barriers were restored without histologic alterations or signs of inflammation. rHuPH20 may function as an interstitial delivery enhancing agent capable of increasing the dispersion and bioavailability of coinjected drugs that may enable subcutaneous administration of therapeutics and replace intravenous delivery.
Bookbinder
L H
LH
Halozyme Therapeutics, San Diego, CA 92121, USA.
Hofer
A
A
Haller
M F
MF
Zepeda
M L
ML
Keller
G-A
GA
Lim
J E
JE
Edgington
T S
TS
Shepard
H M
HM
Patton
J S
JS
Frost
G I
GI
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000917:Antibody Formation / Q000187:drug effects; D001682:Biological Availability; D001693:Biological Transport, Active / Q000187:drug effects; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D016207:Cytokines / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004358:Drug Therapy; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007370:Interferon Type I / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007370:Interferon Type I; D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D006821:Hyaluronoglucosaminidase