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.
Oct 01, 2007

Although subcutaneous (SC) delivery is the preferred way to administer an injected therapeutic, SC injections are limited in the amount of drug substance that can be delivered. Strategies for overcoming this problem are crucial to widening the scope of drugs that may be given subcutaneously. Using a recombinant DNA-derived hyaluronidase enzyme is an approach for possibly changing dosing regimens and bioavailability of several types of agents, including biologics.

Intravenous, intramuscular, and subcutaneous delivery

Intravenous administration. Therapeutic agents can be introduced into the body by several routes of administration with each having specific advantages and disadvantages (see Table I). For many drugs, including biologics and anticancer agents, the traditional route of administration is intravenous (IV). IV injections are given either as a 1-to-2-min-bolus or an infusion with a longer duration to facilitate administering precise doses in a controlled manner or in providing a rapid response. IV dosing is also typical when administering irritating agents such as cytotoxics that would otherwise cause tissue damage and pain if given by alternative routes. IV dosing requires the skilled insertion of a needle or catheter directly into a vein, a process that can be challenging, especially in certain patient types such as obese, palliative-care, and neonate patients. Direct IV access also carries a risk of systemic infection. IV drugs are administered by trained medical personnel in a hospital or physician's office and, because of the rapid effects achieved, patients are typically observed for undesired side effects following injection. This entire process occupies both space in an office and specialized nursing time (1).

Intramuscular injections. When therapeutic regimens require injection volumes in excess of 1 mL, intramuscular (IM) injections are generally chosen. IM injections are given deep into skeletal muscle and usually involve the gluteal, deltoid, rectus femoris, or vastus lateralis muscles. Volumes of 2–5 mL can be administered, and this route is particularly suited for drugs that are not readily soluble, as a sustained depot action is possible (2, 3). Because of the distance from the skin surface into a muscle, IM injections require a relatively long needle (1–2 in.). There is a possibility of hitting a nerve or blood vessel, leading to muscle contractures and nerve injury (3). Because of the needle length and bore size required, IM injections are painful and can temporarily result in limited mobility, an issue of particular concern in older patients (2). IM injections, therefore, are best performed by trained personnel who are familiar with anatomical landmarks, which may be difficult to identify in obese or emaciated patients. Infection is a risk with any parenteral injection because of the risk of bacteria being introduced into the tissue (2, 4–6), which in turn can lead to abscesses and infections in the skin or soft tissue. Other complications of IM injections include local induration, erythema, hematoma, persistent bleeding, and ultimately, drug discontinuation. Less common side effects can include intramuscular hemorrhage, cellulitis, tissue necrosis, and gangrene (7, 8). Although several studies have shown that there are no substantial differences between IM and SC injections in terms of absorption and drug efficacy (2), the absorption rate from an IM injection does depend on blood flow at the injection site and the muscle mass. Also, the rate may be unpredictable in infants because of insufficient muscle tone and vascularity of muscle tissue.

Subcutaneous delivery. During SC administration, a needle is inserted through the epidermal and dermal layers of the skin and into the fatty subcutaneous tissue. Following injection, the drug reaches the bloodstream via the capillaries or the lymphatic system, depending on the molecular size of the therapeutic (2, 3, 9). Large proteins are typically not suited for oral administration, as such drugs would be degraded in the digestive tract and poorly absorbed. Most proteins require SC administration. Large-molecule drugs typically reach the bloodstream through the lymphatic vessels as they move very slowly from the tissues into the capillaries.

SC injections have several immediate advantages over other injection types. In contrast to the skilled personnel required for the administration of IV and IM injections, SC injections can be administered by the patient (2, 3). A small needle is required (length of ⅜–⅝ in.), and the injections are not generally painful and carry a reduced risk of infection and other complications. If an infectious agent is injected subcutaneously, it is generally limited to a local infection rather than a systemic infection. For patients requiring multiple doses, SC injections offer a broader range of alternative sites (3). The resultant drug absorption is also slower than IV and may avoid the risks of bolus administration.