Dosage modeling system

Details Dosage modeling system Dosage modeling system

1999-08-10

2001-09-11

Redding, David A. (Department: 1744)

Chemistry: molecular biology and microbiology

Apparatus

Including condition or time responsive control means

C435S289100, C435S297500

Reexamination Certificate

active

06287848

ABSTRACT:

TECHNICAL FIELD
The present invention describes a monitoring system, more particularly, a dosage modeling system which delivers therapeutic agents (e.g., drugs) to cultured cells in a bioreactor to simulate human pharmacokinetics and pharmacodynamics.
BACKGROUND OF THE INVENTION
Measuring the effect of drug dosage on living tissues is a very difficult and exacting science. Years of research and study may underlie determination of the proper dosage of a drug that will be prescribed to a patient. Drug characteristics are often accumulated using living hosts, such as animals.
The cost inefficiency and limitations of animal models have become pronounced in recent years. For example, it is expensive and time consuming to carry out studies with animals to provide clinical data. Moreover, in some situations, there may be no correlation between the animal model and the effect on a human, or there may be no suitable animal model. For example, certain human viruses are species specific and may have little or no effect on animals at all. The ethics of animal testing has also come into serious question.
The limitations of animal testing have popularized in-vitro studies, wherein dosing of a drug can be tested in an artificial system. For example, an antiviral drug can be tested by culturing or simply placing virus-infected cells into an artificial system which simulates human body characteristics. The cells in the artificial system are exposed to a concentration of the drug throughout the experiment. The artificial system can be used to measure, for example, the drug half-life, i.e., the time required to eliminate half of the quantity of drug that was present in the system relative to the point when the measurement began. The system can also be used to measure other aspects, such as the effectiveness of the drug at various concentrations, and the effect of drug dosing.
These studies are advantageous, as they provide pre-clinical data, which can be evaluated before investing the time and expense needed to provide clinical data. For example, the in-vitro studies can allow a researcher or drug manufacturer to more quickly and economically test a variety of approaches and dosages than would be possible with animal models. As a result, some of the more ineffective drugs and/or approaches can be avoided before clinical studies begin, which can provide a significant savings in both cost and time to the researcher and drug manufacturer.
However, the inventors of the present invention have noticed significant problems in these in-vitro techniques, and have recognized that there is no in-vitro model which is sufficiently representative of the in vivo (living) situation.
For example, one problem with the typical in-vitro system is that it continually exposes the pathogen-infected cells to a fixed concentration of the drug. The infected cells and cellular or viral proteins and nucleic acids are then continuously exposed to constant levels of both the drug and its intracellular metabolites. This dosing model is misrepresentative of the drug dosing that would actually occur in any living system. For example, in a living system, actual drug dosing follows a complicated curve that represents body factors such as absorption rate, the mechanics of how a drug is delivered to a cell, and clearance of the drug.
Additionally, a living system is frequently exposed to two or more drugs, and these drugs may interact in the system. For example, the interaction can be synergistic, whereby doses may be lowered to achieve less side effects from both drugs. Antagonistic drug interactions may be harmful and even fatal. Typical drug dosing models fail to represent the interactions between drugs.
Conventional drug dosing models may inaccurately represent the administered dosage at a particular point in time due to, for example, inadequate mixing of drug and fluid. Additionally, since modeling systems typically administer the drug through tubing, the model may fail to take into account the amount of drug that remains in the end of the tube before the amount reaches sufficient critical mass to fall as a drop. Each drop of drug can be significant, especially when a small volume of drug, and/or a concentrated drug, is used. Alternatively, or additionally, some modeling systems, e.g., that lack check valves, can allow some amount of drug backflow, and thus can fail to accurately represent the administered dosage. Thus, the deficiencies of conventional drug dosing models have prevented drug concentration-over-time/effect relationships in humans from being accurately characterized.
In addition to the disadvantages set forth above, conventional modeling systems use a relatively high volume of fluid, e.g., 100 ml; a relatively low flow rate, e.g., about 1 to 5 ml/min, and the systems require mechanical mixing (magnetic stirrers) and oxygenating coils. As a result, the system is relatively large, which can be undesirable, particularly when space is at a premium. Furthermore, the system is subsequently placed in an incubator to control the temperature of the fluid in the system, so the use of a large incubator is required. Thus, it can be difficult to find sufficient space for the system, or it may be difficult to find a suitably large incubator.
The present invention provides for minimizing or eliminating at least some of the disadvantages of the prior art. For example, the present invention can be used to more accurately evaluate various therapeutic agents to determine an effective dose range and appropriate indications. Embodiments of the invention can be used to provide effective preclinical studies to enhance clinical success. These and other advantages of the present invention will be apparent from the description as set forth below.
SUMMARY OF THE INVENTION
According to the present invention, an in vitro cell perfuision system is described in which both the concentration of one or more therapeutic agents (e.g., drugs and/or drug candidates), and the rate of elimination of the agent(s) can be manipulated and monitored in order to mimic first order human pharmacokinetics. The model of-the present invention can be used to study pharmacokinetics and pharmacodynamics of therapeutic agents such as, but not limited to, antiviral agents, antimicrobial agents (e.g., antibiotics), antineoplastic agents, antiarrhythmic drugs, cardiovascular drugs (e.g., antihypertensive drugs), antiinflammatory agents, immunosuppressive agents, immunostimulatory drugs, drugs used in the test of hyperlipoproteinemias, and asthma, drugs acting on the central nervous system (CNS), hormones, hormone antagonists, vitamins, hematopoietic agents, anticoagulants, thrombolytic and antiplatelet drugs. The model can also be used in toxicity studies, including toxicity studies involving metals, metal antagonists, and non-metal toxicants.
The relationship between the dose of a drug given to a patient and the utility of that drug in treating the patient's disease is described by two fundamental areas of pharmacology-pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetics concerns the absorption, distribution, biotransformation (metabolism, if it exists), and the elimination of drugs, i.e., what the body does to the drug. Relevant pharmacokinetic terms include C
max
, the peak (maximum) concentration; AUC, the area under the drug concentration-time curve; T
max
, the time of peak drug concentration; Cl (clearance rate), the measure of the body's ability to eliminate the drug (volume per unit time); volume of distribution, the ratio of the amount of drug in the body to the concentration of the drug in the blood; and C
min
, the concentration before the next dose is administered.
Pharmacodynamics is the study of the relationship between drug concentration and intensity of pharmacological effect, i.e., what the drug does to the body. Relevant pharmacodynamic terms include E
max
, the maximum effect, ED
50
, the dose which produces 50% of the maximum effect, and EC
50
, the concentration observed at half the maximal effect.
In accordance with the pre

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