Converting Intravenous Dosing to Subcutaneous Dosing With Recombinant Human Hyaluronidase - Pharmaceutical Technology

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Converting Intravenous Dosing to Subcutaneous Dosing With Recombinant Human Hyaluronidase
The preferred route of administration for an injected therapeutic agent is subcutaneous (SC), but SC injections are generally limited to no more than 1-2 mL in volume, representing a major challenge, especially for large protein biologics.

Pharmaceutical Technology

From many perspectives, including reduced pain, improved patient quality of life, reduced cost of patient care, and reduced risk of infection, SC represents a preferred route for administering a drug by self-injection. Many drugs, including insulin and heparin, have been delivered subcutaneously for many years with excellent outcomes. In a recent survey by Lash Group Healthcare Consultants of oncology practices across the country, there is a conscious shift to SC administration (1). Compared with IV drugs, the majority of participants in the survey considered SC drugs clinically safer and more cost-effective, resulting in higher patient satisfaction.

Subcutanous versus intravenous. It can be enlightening to compare the actual administration costs of a drug that can be delivered by both IV and SC routes. Campath (alemtuzumab) is a recombinant humanized monoclonal antibody directed against CD52 for treating B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and who have failed fludarabine therapy (10). The drug is delivered by IV and SC routes. The cost of supplies required for IV administration are substantially more than those required for SC administration (1). The staffing requirements for IV administration (2–6 h of observation) are higher than those of SC injections (0.5–1 h). Also, the associated costs are not captured in the reimbursed allowables and represent a hidden cost.

Figure 1: Revenues of intravenous (IV)- versus subcutaneous (SC)-administered anti-TNF-alpha treatments (2001–2006). (FIGURES: HALOZYME THERAPEUTICS)
The anti-TNF-alpha treatments for rheumatoid arthritis and Crohn's disease are also good examples of the relative desirability of SC versus IV administration. Centocor's Remicade (infliximab) is an antibody that is administered intravenously, and Amgen's Enbrel (etanercept) and Abbott Laboratories' Humira (adalimumab) are both given subcutaneously. Efficacy differences between all three drugs when administered with methotrexate are considered minimal (11). A broad indicator, such as revenues (see Figure 1) shows that IV- and SC-delivered agents were essentially equal in 2001, and both have been growing at healthy rates. The relative growth rate of the SC agent, however, is approximately 50% higher than that of the IV drug (a 33% compound annual growth rate for IV versus 50% for SC), translating into 2006 revenues for the SC agent that are almost double that of the IV agent. This increase occurred despite reimbursement dynamics for SC injectables that were unfavorable until recently (12).

Table I: Intravenous, intramuscular, and subcutaneous injections: advantages and disadvantages.
Limitations in subcutanous administration. Given the advantages of SC administration, the question can be asked: Why are there are not more SC injectable protein agents on the market? This situation may be attributed to several well-known disadvantages associated with SC injections (see Table I). One disadvantage is that SC injections are generally limited to no more than 1–2 mL (3). Several ways to circumvent these volume limitations, including increasing the concentration of the active ingredient in the formulation, have been pursued. For proteins, resultant issues of viscosity, solubility, and protein aggregation become major obstacles, especially with small-gauge needles that are typically preferred by the patient. For agents of limited solubility such as monoclonal antibodies, large volumes must be injected via frequent, small-volume injections. Additionally, at the injection site, some drugs are trapped and locally degraded, leading to lowered bioavailability, and others can be retained at high concentrations, which sometimes leads to concentration-dependent adverse reactions or reduced bioavailability. These issues are challenging problems for converting IV- and IM-dosing to SC regimens.

At the heart of the volume limitations of SC injections are collagen and hyaluronan, two major components of the subcutaneous interstitial matrix.


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