Therapeutic protein administration routes

While some parenteral injections, such as intravenous administration, provide rapid and predictable access to the circulation and tissues, therapeutic proteins are rapidly cleared from the system, and thus such administrations may result in very short durations of action. Regardless of route of administration, therapeutic proteins may exhibit limited distribution outside of endothelial cells lining blood vessels. This may be advantageous for thrombolytic agents, such as tissue plasminogen activator, which is used for rapid fibrinolytic actions at... 

To modulate the rate and extent of therapeutic protein exposure in target tissues, scientists have considered other routes of administration. These alternative routes of drug delivery will be discussed below. All available data suggest that protein bioavailability is expected to be low for nonparenteral routes of administration (i.e., less than 10%). 

Most therapeutic proteins and peptides are formulated as solution or suspensions for injection (i.e., intravenous, subcutaneous, intramuscular, intraperitoneal, intravitreal, or intrathecal). These routes of administration are described in Table 5.5. Parenteral administration provides a more predictable therapeutic profile than oral administra-... 

The route of administration influences the likelihood of an antibody response independent of the mechanism of induction. The probability of an immune response is the highest with subcutaneous administration, less probable after intramuscular administration and intravenous administration is the least immunogenic route. There are no studies comparing parenteral and nonparenteral routes of administration. Flowever, as both mucosal tissues and the skin are immune competent organs designed to keep invaders out of the body, intranasal, pulmonary, and transdermal administration of therapeutic proteins may increase the risk of an immune response as compared to parenteral routes. 

Figure 14.1. Fate of plasmid DNA in vivo after intravascular (left) or tissue (right) injection. Upon administration, plasmid DNA can be taken up by various cells, including mononuclear phagocytes such as macrophages. It also interacts with plasma proteins and extracellular matrix (ECM) components. In some cases, extravasation (intravascular route) or diffusion (tissue injection) is required for plasmid DNA to reach the target cell. Cellular uptake of DNA occurrs via an endocytotic route (solid lines) as well as a nonendocytotic route (dashed lines), depending on the vector and delivery method used for gene transfer. When endocytosis occurs, a means of endosomal escape is needed. Only plasmid DNA entering the nucleus has a chance to produce therapeutic protein.

When administered via SC, intramuscular, or inhalation routes, the bioavailability of therapeutic proteins is variable and the fraction absorbed is dependent on the molecular weight of the protein (47). Interferon alpha, which is a relatively low molecular weight protein (19 kD), has good bioavailability following SC administration (80%), whereas most therapeutic monoclonal antibodies have bioavailability of approximately 20-60% following SC administration. 

Also the treatment characteristics can have an influence on the immunogenicity of therapeutic proteins. Usually antibodies are only induced after prolonged treatment of the protein. The intramuscular (i.m.) route of administration is less immunogenic than subcutaneous (s.c.) administration. Intravenous (i.v.) administration usually is the least immunogenic route of administration. 

The transdermal route of agent administration could be advantageous in the delivery of many therapeutic proteins, because proteins are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, and transdermal devices are more acceptable to patients than injections. 

Therapeutic proteins and peptides have gained a significant market interest owing to their increased development and applicability to multiple disease conditions (Chin et al., 2012 Park et al., 2011). For the systemic delivery of therapeutic peptides and proteins, parenteral administration is currently believed to be the most efficient route and also the delivery method of choice to achieve therapeutic activity compared with transdermal, pulmonary, nasal, oral, and buccal delivery routes (Fig. 11.4) (Muranishi, 1985 Lennemas, 1995 Ghilzai, 2004). But, for the usually faced chronic conditions, patients find the use of daily injections both unpleasant and difficult to be self-administered. 

Among the various routes for gene therapy, the oral route is yet again the most attractive due to the ease of administration and high patient compliance. Efficient oral gene therapy provides an unparalleled opportunity for sustained production of therapeutic protein locally at the disease site in the gastrointestinal (GI) tract or at a site where maximum systemic absorption can occur due to increased residence and low proteolytic activity. Sustained production of therapeutic proteins in the GI tract has... 

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