Bioavailability of large co-injected proteins
The available data indicate that when co-injected with rHuPH20, molecules should be dispersed more thoroughly. This situation
should lead to increased exposure to capillary beds and lymphatics and greater bioavailability. This approach was evaluated
in a rodent model using a 31-kDa pegylated cytokine (peginterferon alfa 2b) and a 149-kDa monoclonal antibody (infliximab)
(38). As shown in Figures 5a and 5b, respectively, local co-injection with rHuPH20 increased the absolute bioavailability
and Cmax (the maximum concentration of a drug in the systemic circulation after dosing) of the cytokine (bioavailability: 61% was
increased to 108%,p (p value) <0.001; Cmax: 61,782 to 121,750 CPM (counts per minute)/g, p <0.0003), and the antibody (bioavailability: 59% was increased to 94%, p <0.00001; Cmax: 531,866 to 875,369 CPM/g, p <0.00002). rHuPH20 is clearly able to improve the pharmacokinetic profiles of co-injected drugs compared with the pharmacokinetics
typically observed following IV administration. This improved profile results in increased bioavailability. As large drugs
typically access the systemic circulation through the lymphatic vessels, it appears that rHuPH20 may be exerting an effect
on bulk-liquid flow through the draining lymphatics.
Figure 5: Pharmacokinetic parameters of a pegylated cytokine and a monoclonal antibody that were co-injected with either placebo
or with rHuPH20: (a) bioavailability (area under concentration versus time curve [AUC] as a percentage of intravenous [IV]) and (b) Cmax (the maximum concentration of a drug in the systemic circulation after
dosing). CMP is counts/min. (FIGURES: HALOZYME THERAPEUTICS)
For large protein biologics such as monoclonal antibodies, volume and bioavailability constraints must be overcome before
subcutaneous injections can mirror intravenous (IV)-like dosing regimens. While "spreading factors" have been exploited clinically
for many years, the problems associated with such animal-derived agents have limited their use, particularly in the chronic
setting. The discovery of the human hyaluronidase gene family and the molecular engineering of a purified soluble human rDNA-derived
PH-20 hyaluronidase enzyme (rHuPH20), however, have propelled the clinical development of an enzyme-mediated drug-delivery
system. Data indicate that molecules as large as 200 nm in diameter were readily dispersed when co-injected with rHuPH20 and
resulted in markedly reduced tissue distortion. The pharmacokinetic profiles of molecules co-injected with rHuPH20 showed
a higher Cmax (the maximum concentration of a drug in the systematic circulation after dosing) and earlier Tmax (the time to Cmax) than those co-injected with carrier controls. Systemic bioavailability of large molecules typically absorbed by the lymphatic
route was significantly increased with rHuPH20 co-injection, leading to profiles approaching those achieved with IV dosing.
rHuPH20 represents a broad platform technology for potentially altering the dosing regimens and bioavailability of many agents,
including biotechnology-derived proteins.
The author would like to acknowledge the work completed by Halozyme Therapeutics' research staff, especially Gregory Frost,
PhD, who is chief scientific officer, director, and vice-president of Halozyme Therapeutics.
Michael F. Haller, PhD, is vice-president of alliance management and portfolio development at Halozyme Therapeutics, 11388 Sorrento Valley Road,
San Diego CA 92121, tel: 858.704.8211, firstname.lastname@example.org
Submitted: July 19, 2007; Accepted Aug. 8, 2007.
1. D. Gilbert and & D. Cothran, "SC versus IV Delivery: Reducing Costs while Increasing Patient Satisfaction," Hematology & Oncology News & Issues, Dec. 25–27, 2005.