Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
2001-08-03
2004-10-26
Chin, Christopher L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C385S012000, C385S129000, C385S130000, C356S418000, C422S082110, C435S007100, C435S007200, C435S007400, C436S164000, C436S165000, C436S524000, C436S525000, C436S527000, C436S528000, C436S529000, C436S805000
Reexamination Certificate
active
06808938
ABSTRACT:
TECHNICAL FIELD
This invention is generally directed to a method and apparatus for assaying a drug candidate and, more specifically, to a method for measuring the binding interaction between a drug candidate and sensing surface-bound biomolecules of a biosensor to determine a binding interaction parameter of the drug candidate, and then comparing the binding interaction parameter against a predetermined drug correlation graph (e.g., a mathematical expression) to estimate at least one pharmacokinetic parameter.
BACKGROUND OF THE INVENTION
A variety of experimental techniques are currently used to determine chemical, physical and biological properties associated with low molecular weight substances, particularly in the context of drug discovery. For example, researchers are often concerned with determining a variety of chemical, physical and biological properties associated with drug candidates for screening purposes. The determination of such properties often plays a pivotal role in the drug development and screening process.
More specifically, it has long been recognized that the intensity and duration of the pharmacological effect of a systemically acting drug are functions not only of the intrinsic activity of the drug, but also of its absorption, distribution, metabolism, and excretion (ADME) characteristics within the human body. These so-called ADME characteristics are all intimately related to the scientific discipline known as “pharmacokinetics.” Pharmacokinetics is commonly referred to as the study of the time courses (i.e., kinetics) associated with the dynamic processes of ADME of a drug and/or its metabolites within a living organism, and is closely interrelated with the fields of biopharmaceutics, pharmacology, and therapeutics.
Because the body delays the transport of drug molecules across membranes, dilutes them into various compartments of distribution, transforms them into metabolites, and eventually excretes them, it is often difficult to accurately predict the pharmacological effect of promising new drug candidates. Researchers, however, commonly use pharmacokinetic ADME studies as one method to predict the efficacy of a drug at a site of action within the body.
Traditionally, researchers involved with preclinical ADME studies have used pharmacokinetic/mathematical models coupled with actual drug concentration data from blood (or serum or plasma) and/or urine, as well as concentration data from various tissues, to characterize the behavior and “fate” of a drug within living organisms. As is appreciated by those skilled in the art, the mathematical equations associated with pharmacokinetics are generally based on models that conceive the body as a multicompartmental organism. In such models it is presumed that the drug and/or its metabolites are equitably dispersed in one or several fluids/tissues of the organism. Any conglomerate of fluid or tissue which acts as if it is kinetically homogeneous may be termed a “compartment.” Each compartment acts as an isotropic fluid in which the molecules of drug that enter are homogeneously dispersed and where kinetic dependencies of the dynamic pharmacokinetic processes may be formulated as functions of the amounts or concentrations of drug and metabolites therein. Stated somewhat differently, the conceptual compartments of the body are separated by barriers that prevent the free diffusion of drug among them; the barriers are kinetically definable in that the rate of transport of drug or metabolite across membrane barriers between compartments is a function of, for example, the amounts or concentrations of drug and metabolites in the compartments, the permeability of various membranes, and/or the amount of plasma protein binding and general tissue binding.
More specifically, pharmacokinetic/mathematical models are commonly used by pharmacokineticists to represent drug absorption, distribution, metabolism, and excretion as functions of time within the various tissues and organs of the body. In such models, the movement of the administered drug throughout the body is concisely described in mathematical terms (e.g., a set of differential equations). The predictive capability of such models lies in the proper selection and development of mathematical functions that parameterize the essential factors governing the kinetic process under consideration.
For example, a drug that is administered by intravenous injection may be assumed to distribute rapidly in the bloodstream. A pharmacokinetic/mathematical model that describes this situation may be a tank containing a volume of fluid that is rapidly equilibrated with the drug. Because a fraction of the drug in the body is continually eliminated as a function of time (e.g., excreted by the kidneys and metabolized by the liver), the concentration of the drug in the hypothetical tank may be characterized by two parameters: (1) the volume of fluid in the tank that will dilute the drug, and (2) the elimination rate of the drug per unit of time, both of which are generally considered to be constant. Thus, if a known set of drug concentrations in the tank is determined at various time intervals by, for example, sampling, then the volume of fluid in the tank and rate of drug elimination may be estimated. This information may then, in turn, be used for predicting the disposition of the drug within a human body.
Theoretically, an unlimited number of models may be constructed to describe the kinetic processes of drug absorption, distribution, metabolism, and excretion within the various tissues and organs of the human body. In general, however, the number of useful models is limited due to practical considerations associated with blood, tissue and/or organ sampling. As a result, and as is appreciated by those skilled in the art, two major types of models have been developed by pharmacokineticists: (1) compartmental models; and (2) physiologic models.
In pharmacokinetic compartmental models, the body is represented as a series of compartments that communicate reversibly with each other. Each compartment is not a real physiological or anatomic region; rather, each compartment is considered to be inclusive of all tissues that have similar blood flow and drug affinity. For example, a compartmental model may consist of one or more peripheral compartments representing tissue(s) connected to a central compartment representing the blood stream. Conceptually, the drug moves dynamically into and out of the central compartment and into and out of each of the peripheral compartments. As such, rate constants may be used to represent the overall rate process for the drug's disposition within each compartment. Compartment models are generally based on linear assumptions using linear differential equations, and are particularly useful when there is little information known about the tissues and their respective drug concentrations.
In contrast, pharmacokinetic physiologic models are based on known anatomic and physiologic data, data which is kinetically described in view of the actual blood flow volumes responsible for distributing the drug to the various parts of the body. Because there are many tissue organs in the body, each tissue volume must be estimated and its drug concentration and rate of change described mathematically (tissues having similar blood perfusion properties, however, are typically grouped together). Unfortunately, much of the information required to adequately describe such pharmacokinetic physiologic models are often very difficult to obtain experimentally. Nevertheless, such physiologically based models are commonly used in conjunction with animal data and interspecies scaling techniques to predict the drug's disposition within a human body.
More importantly, however, is that pharmacokinetic/mathematical models, and knowledge of their associated ADME parameters play an extremely important role in drug discovery and development. A typical example is a drug that is active following intravenous administration but is considerably less active after comparable oral doses. Having
Hämäläinen Markku
Karlsson Robert
Löfås Stefan
Biacore AB
Chin Christopher L.
Seed IP Law Group PLLC
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