Summary

• Hyaluronidases are a family of glycosaminoglycan-degrading enzymes that hydrolyze hyaluronan in the extracellular matrix (ECM) of the hypodermis. Recombinant human hyaluronidase (rHuPH20) is a purified form of testicular (PH20) hyaluronidase, which does not elicit immunogenic reactions.^1-4
• When administered subcutaneously (SC), rHuPH20 hydrolyzes hyaluronan in the ECM. This results in a lowered viscosity of hyaluronan and the SC space and a consequent increase in tissue permeability, thus reducing the barrier to dispersion and absorption of co-administered drugs.^1,4,5
• rHuPH20 can be co-administered as an adjuvant, either sequentially or concomitantly, with a therapeutic drug for SC delivery, facilitating the dispersion of the drug and improving its infusion and absorption rates and bioavailability.^1,4-7

Overview

Hyaluronidases are a family of glycosaminoglycan-degrading enzymes that catalyze the hydrolysis of hyaluronan.^1-3,8 Hyaluronidases, predominantly PH20, purified from bovine or ovine testes, have been clinically used to facilitate the permeation and absorption of SC-administered drugs. However, their utility is restricted by their impurity profiles and their propensity to cause immunoglobulin E-mediated immune hypersensitivity reactions upon repeated use.^1-3,7

rHuPH20 is a purified form of hyaluronidase, with an approximately 100 times greater purity than the animal testes-derived hyaluronidase, thus reducing the risk of allergies and transmission of diseases from animalderived ingredients and allowing for broader therapeutic applications in patients, including repeat dosing/chronic administration.^1,4,5,7,9 It contains amino acids 1-48 of hyaluronidase and acts at a neutral pH under physiologic conditions without eliciting inflammation, vascular permeability, or immunogenic reactions.^1,2,7,9

BACKGROUND

Drugs administered SC must permeate the ECM of the hypodermis to reach the vascular compartment.^1-3 The rate of permeation is impeded by the ground substance of the ECM, composed of glycosaminoglycans such as hyaluronan, which creates a gel-like, viscous, and hydrated barrier to drug flow at the SC injection site.^1-4 This limits the SC injection volume and causes retention of drugs within the hypodermis, resulting in injection-site reactions and reduced bioavailability of the injected drug.^1-3,6,7

Glycosaminoglycans are complex linear polysaccharides characterized by repeating disaccharide structures of an N-substituted hexosamine and a uronic acid. Hyaluronan is the principal glycosaminoglycan of the hypodermis among chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, and keratan sulfate, and is the only component that is not bound covalently to core proteins.^2,3,9

Mechanism of Action

When administered SC, rHuPH20 hydrolyzes the N-acetylglucosamine and glucuronic acid bond, leading to depolymerization of hyaluronan in the ECM.^1,4-6,10,11 This results in a lowered viscosity of hyaluronan and the SC space, a switch in transport of proteins in the space from diffusion to bulk fluid flow, and a consequent increase in tissue permeability, thus reducing the barrier to dispersion and absorption of co-administered drugs and enabling faster and larger volumes of delivery to the SC space. The action of rHuPH20 is transient and reversible, as hyaluronan in the ECM is reconstituted within 24-‍48 hours.^1,2,5,7,11

rHuPH20 specifically acts on hyaluronan and therefore does not degrade the collagen within the ECM, thus preventing distortion of the SC tissue. Additionally, rHuPH20 neither increases the vascular permeability nor elicits an immune response or leukocyte infiltration.^1,2,7

Pharmacokinetics

Using a method combining 2-aminobenzamide (2-AB) labeling with size exclusion-ultra performance liquid chromatography (SE-UPLC), it was determined that rHuPH20 followed Michaelis-Menten kinetics in its initial reaction time. The rHuPH20 kinetic parameters were not significantly affected by the hyaluronan substrate size.¹⁰

rHuPH20 is rapidly cleared from the blood after injection and has a terminal elimination half-‍life of 5-6 minutes.^7,8

Clinical Implications

rHuPH20 can be co-administered as an adjuvant, either sequentially or concomitantly, with a therapeutic drug for SC delivery.^5-7 Co-administration of rHuPH20 with a therapeutic drug has the following clinical implications:

• rHuPH20 facilitates the dispersion of and improves the infusion and absorption rates of co-administered SC drugs, resulting in a shorter administration time.^1,4,8
• rHuPH20 permits administration of up to 5 times more volume of SC-administered drugs and at an individualized rate, thus possibly reducing the frequency of administration. rHuPH20 also enables administration at the preferred injection site, with minimal distortion of the SC tissue, thus reducing injection-site pain.^1,6-8,12
  • No allergic reactions were reported with intradermal injection of rHuPH20.⁵ Although rHuPH20-induced and -boosted binding antibodies have been reported, there was no association between these and the incidence of adverse events.⁷
• rHuPH20 significantly improves the pharmacokinetic (PK) profile of drugs coadministered by the SC route.¹
  • rHuPH20 increases the absorption rate of co-administered drugs by enabling greater permeation of the drug through the SC space. This allows a more rapid access to the central circulation via a greater surface area of capillaries and lymphatics exposed to small- and large-molecule therapeutics, respectively.^1-3,7,12
  • rHuPH20 enhances the systemic bioavailability of locally injected biotherapeutics. The PK profile of drugs when administered with rHuPH20 showed a higher maximum serum concentration (C_max) and shorter time to reach C_max (T_max) than when administered with carrier controls.^1,2,6

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 11 December 2024.