Interstitial Fluid Composition

Because of arteriole-to-venule pressure differences, there is a physical force for serum fluid and solute components to exit capillary beds and enter the SC space (18). Active and passive uptake mechanisms present in venules recover most, but not all, of what is lost from these capillary beds. The absorptive function of lymphatic structures is critical in maintaining the overall volume influx efflux equilibrium within the SC space. Proper organization of vascular and lymphatic elements within...

Comparison of SC to Intramuscular and Intradermal Injections

Although the primary focus of this chapter was to discuss issues associated with SC injection or protein and peptide therapeutics, it is also possible to inject these molecules directly into muscle tissue or into the dermis of the skin. Intradermal (ID) injections are best known for the cosmetic application of collagen (114), while intramuscular (IM) injections are frequently used to administer vaccines. Because of unique biological outcomes, ID injections have also been used successfully for...

Intersection Between Stratified Medicine and Targeted Therapies

Genetic variability may affect the PK and PD of protein therapeutics and may thus have the potential to affect patient responses. To achieve broader utilization of Pgx tools, it is critical that the scientific community understand what such information will really bring to clinical practice. Individualized medicine has received great publicity in recent years, with articles forecasting the use of genomic tests to tailor new drugs and provide patients with targeted treatment. Although this type...

Effect of Interferona2b on Methadone Pharmacokinetics

Methadone, a racemic mixture, is primarily metabolized by CYP3A4, secondarily by CYP2D6, and to a lesser extent by CYP1A2 and CYP2B6 (18). Gupta et al. (24) evaluated the effects of multiple doses of peg-IFN-a2b (PEGASYS) on the steady-state pharmacokinetics of methadone in patients with hepatitis C. Twenty adults with hepatitis C virus infection received peg-IFN-a2b (1.5 mg kg wk) SC for four weeks and maintained their normal methadone regimen (approximately 40 mg day). There was approximately...

Tissue Responses At A Subcutaneous Injection Site Events Stimulated by Needle Penetration at Injection

Following withdrawal, large-diameter needles can produce a wound that is not immediately closed by the elastic nature of the epidermis use of large-diameter needles can result in the loss of some material leaving the SC injection site because of back pressure. This is one reason small gauge needles are preferred for SC injections. Another reason is that larger needles are likely to come in contact with a greater number of pain-registering nerves than a smaller needle. Further, needle lengths...

IgE as a Target to Treat Allergic Asthma

Anti-IgE mAbs provide immunological examples wherein in vitro data have been correlated to in vivo PK and PD, as a measure of in vivo potency. Omalizumab (Xolair , rhuMAb-E25) is a humanized IgG1 anti-IgE mAb used in the treatment of moderate to severe allergic asthma. This Ab suppresses serumfree IgE levels by selectively binding to IgE, forming small, biologically inert immune complexes (95). By blocking the binding of IgE to high-affinity FceRI, the Ab inhibits cross-linking of IgE bound to...

Drugs And The Pharmaceutical Sciences

A Series of Textbooks and Monographs PharmaceuTech, Inc. Pinehurst, North Carolina University of Maryland Baltimore, Maryland University of Frankfurt Institute of Pharmaceutical Technology Frankfurt, Germany University of North Carolina School of Pharmacy Chapel Hill, North Carolina GlaxoSmithKline Research Triangle Park North Carolina University of Florida Gainesville, Florida University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom Center for Pharmaceutical Physics...

Dosage Form Design Protecting Protein Peptide Drugs from GI Metabolism

Cyclosporine is reported to have a relatively high oral bioavailability (> 30 ) and provides an example where the drug is relatively stable from metabolic degradation in the GI tract. In contrast, drugs that are susceptible to being degraded in the GI tract would typically result in low bioavailability, with a high degree of variability. As such, strategies to protect the protein and peptide drugs from degradation in the GI tract can further enhance oral bioavailability. Various strategies...

Dilution of Interstitial Fluid Composition and Return to Steady State Conditions

Although the concentration of endogenous interstitial fluid elements is typically overwhelmed at the site of an SC injection, the body sets in motion a series of processes to ensure the rapid recovery of its steady-state composition. Various factors, in particular the composition of the injected formulation and the injection volume, will drive the rate of protein or peptide therapeutic absorption. One can envision that at the time of SC injection, there is a transition from an initial...

Effects of Upstream and Downstream Processes

Beyond the interaction of the drug with its target, variations in downstream effector pathways such as signaling proteins and transcription factors may influence the overall action of the treatment. We recently published a comprehensive review of Pgx studies of mechanistically related candidate markers in drug target pathways for protein therapeutics (15). A few examples are provided to illustrate the effects of downstream processes on drug responses. One example illustrating this effect...

Nonspecific Vs Specific Uptake

The rate and extent of nonspecific solute uptake into capillaries from an SC injection site is controlled by the net difference in driving forces between the interior and exterior of these vessels along with the relative permeability of the vascular and lymph membranes (93). There are three basic forces that determine the balance of nonspecific solute exit and entry capillary pressure, interstitial fluid pressure, and oncotic pressure (94). Capillary pressure, produced by the beating heart,...

Immunogenicity Predictions Development of Antidrug Antibody Responses

Protein drugs are known to elicit immune responses in patients. Immunoge-nicity was first detected a century ago with therapeutic proteins of animal origin, such as bovine and porcine insulin for the treatment of diabetes (118). Although recombinant technologies now produce proteins using fully human sequences, some patients still develop antibodies. Therapeutic proteins are often engineered with regions of nonnatural sequence. Novel sequences, or the novel presentation of endogenous sequences,...

In Vitro Binding Correlated To In Vivo Properties

In vitro cell-binding experiments employ highly simplified model systems lacking the physiological complexities of living organisms. This distinction underscores a critical uncertainty that trends observed in binding to cultured cells expressing the target antigen alone may or may not necessarily translate into the same trend with respect to targeting, efficacy, or other in vivo behaviors. In some regards, in vitro models are best-case scenarios in which the chances are stacked in favor of...

Clinical Consequences of the Effects of Interferons on the CYP450 System

The aforementioned studies provide some evidence that type I IFNs may inhibit or induce hepatic drug metabolism in humans and there may be some potential of toxic drug-drug interactions. However, the studies also indicate that inhibition or induction may not be of any clinical significance mainly because of the high variability and bidirectionality inhibition in some subjects and induction in some . Because of limited number of interaction studies and since these studies were only short-term...

Mechanism of Type I Interferon Inhibition of CYP450 System

The mechanism by which type I IFNs inhibit the CYP450 system is not well understood. It has been postulated that increased degradation of CYP450 apo-protein may be the reason for depressed enzymatic activity 28 . It is also possible that type I IFNs increased the synthesis of xanthine oxidase, which in turn produces superoxide that destroys CYP450 29 . Some investigators 30-32 have suggested that high antiviral or antitumor activity of these IFNs through the biochemical pathways that mediate...

Hepatic Elimination

The liver plays an important role in the removal of proteins from the systemic circulation. Uptake of peptides and proteins from the blood into hepatocytes occurs by two mechanisms 9 receptor-mediated endocytosis RME and non-selective pinocytosis RME can lead to saturable clearance or nonlinear pharmacokinetics for peptide and protein drugs 3 . In RME, circulating proteins are taken up by specific hepatic receptors 9 . Insulin and epidermal growth factor are examples of RME. Receptor-mediated...