Multicellular living organisms and unmodified parts thereof and – Method of using a transgenic nonhuman animal in an in vivo...
Reexamination Certificate
1998-12-28
2001-04-24
Brusca, John S. (Department: 1631)
Multicellular living organisms and unmodified parts thereof and
Method of using a transgenic nonhuman animal in an in vivo...
C424S078170, C435S006120, C435S029000, C536S023400
Reexamination Certificate
active
06222093
ABSTRACT:
1. INTRODUCTION
The field of this invention relates to methods for assessing or determining the relative therapeutic efficacy versus toxicity of a drug. Specifically, this invention provides methods for evaluating the efficacy and toxicity of a drug by examining the effect of the drug on a target gene expression pathway versus that on off target gene expression pathways. In addition, this invention also provides methods for pharmacodynamic monitoring of drug therapy in individual subjects.
2. BACKGROUND OF INVENTION
The goal of drug discovery is to develop a safe and effective drug. However, most drugs cause adverse reactions in patients. Nies and Spielberg, 1996, Principles of Therapeutics, in T
HE
P
HARMACOLOGICAL
B
ASIS OF
T
HERAPEUTICS
, (Hardman and Limbird, eds.), McGraw-Hill: New York. The benefits of a drug, therefore, must be evaluated based upon the anticipated benefits and potential adverse reactions. Id. The current methods for assessing safety and efficacy, however, are insufficient to meet the demand of ever increasing speed of drug discovery and individual drug therapy decision making.
2.1. Pharmacological Indicators
Various pharmacological indicators have been developed to evaluate drug efficacy and toxicity. Both potency and toxicity of a drug can be evaluated using dose response curves. A dose response curve is a graphic representation of the relationship of dose of a drug applied to a subject versus the response of a subject to the drug (beneficial or toxic effect). Many pharmacological indicators are based upon dose response curves.
Two distinct types of dose response curves are used for estimating various pharmacological indicators. A “graded response curve” depicts a response of an individual subject to varying doses of a drug. A continuously increasing response up to a maximum can be achieved as doses of a drug are increased. A graded response curve is typically a hyperbolic curve. If the dose is in a logarithmical scale, a graded response curve is generally a S-shaped curve. Graded response curves are generally for analyzing individual responses.
A quantal dose response curve is a graphic representation of cumulative frequency of number of subjects responding versus the dose in logarithmic scale. Several important pharmacological indicators are calculated according to the distribution of responding subjects, i.e., the quantal response curve. Medium effective dose (ED
50
) is the dose at which 50% of the population expresses a specified response. Medium lethal dose (LD
50
) is the dose at which 50% of the population dies. Medium toxic dose (TD
50
) is the dose at which 50% of the population expresses a specified toxic effect.
One particularly useful pharmacological indicator is the therapeutic index which is traditionally defined as the ratio of LD
50
to ED
50
or the ratio of TD
50
to ED
50
. Therapeutic index provides a simple and useful indicator of the benefit versus adverse effect of a drug. Those drugs which have a high therapeutic index have a large therapeutic window, i.e., the drugs may be administered over a wider range of effective doses without incurring significant adverse events. Conversely, drugs having a small therapeutic index have a small therapeutic window (small range of effective doses without incurring significant adverse events). Treatment with a drug having a small therapeutic window requires close monitoring.
However, pharmacological indicators, such as the therapeutic index defined above, are often impractical for several reasons. First, as discussed above, those pharmacological indicators are generally determined from the effect of a drug or drug candidate on a population (from quantal response curves), a determination of the above described therapeutic index requires extensive animal or clinical experiments. Such experimentation can be lengthy and costly. Secondly, in vitro experiments, particularly clinical trials, are often conducted at the late stage of drug development. Because of the late stage evaluation, a great expense could incur in researching a drug candidate only to find that the drug candidate has a very low therapeutic index (small therapeutic window).
Therefore, it would be a significant benefit to be able to evaluate the safety and efficacy of a drug candidate during early stages of lead compound selection in drug discovery. Accordingly, this invention provides methods for evaluating drug safety and efficacy that are suitable for early screening of drug candidates.
2.2. Drug Effect in Individuals
Pharmacological indicators, such as the therapeutic index defined above, are only pertinent to a population. The efficacy and toxicity of a drug to an individual, however, may vary due to a number of factors such as genetic variations, and changing physiological or pathological conditions. A “safe” and “effective” drug to a population with a low therapeutic index may become deadly to an individual. Conversely, a drug with a low therapeutic index may be highly effective with tolerable side effects in some individuals.
In a clinical setting, a physician must select, among several drugs, the most effective and safe drug for the patient. In making this decision, the physician needs to know how an particular patient may respond to a drug. One approach to individualized therapy decision making is through pharmacogenetics which relates individual variation in drug response to genetic variations. Pharmnacogenetics promises a better understanding the relationship between genetic variation and drug responses. However, so far, it has only provided limited information related to about 50-100 known drug metabolizing genes. In addition, pharmacogenetics does not address a patients' physiological or pathological conditions.
The second approach is to monitor the clinical symptoms of a patient under drug therapy. This approach is not very effective because signs of toxicity and other effects are often difficult to recognize. See, Yatscoff, et al., 1996, Pharmacodynamic Monitoring of Immunosuppressive Drugs. T
RANSPLANT
. P
ROC
., 28:3013-3015.
The third approach is to assess the pharmacokinetics, i.e., drug distribution of individual patients. The problem of this approach is that drug concentration may not correlate well with drug effects.
More recently, pharmacodynamic monitoring, which involves the measurement of biological effect of a drug, has been applied to the monitoring of individual patients under drug therapy. In one such clinical experiment, adult bone marrow transplant patients were treated with cyclosporine A (CyA). Pai et al., 1994, Blood 82:3974. The activity of calcineurin (CN), a serine-thronine phosphatase that has an essential role in calcium-dependent signal transduction, was monitored in those patients as an indicator of drug action. The activity of CN, however, was found not to be highly correlated with the effect of the drug. Another problem of the current pharmacodynamic monitoring approach is that only one or few enzymes are monitored. Drug actions, however, are often extensive, directly or indirectly affecting many different pathways.
Therefore, there is a great need for methods useful for monitoring drug actions in individual patients. Accordingly, this invention provides methods useful for monitoring both the beneficial and the toxic effects of a therapeutic regimen during treatment, e.g., to determine optimum doses for a patient which are both safe and effective to that patient.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
3. SUMMARY OF THE INVENTION
This invention provides methods for evaluating drug efficacy and toxicity. These methods are particularly suitable for evaluation of drug candidates in the early phases of drug discovery. The methods of the invention are also useful for determining the most suitable doses for a particular patient (an animal or a human).
This invention is partially based upon the ability to detect specific actions of a drug on biological pathways. A target pathway of a dr
Marton Matthew
Stoughton Roland
Brusca John S.
Pennie & Edmonds LLP
Rosetta Inpharmatics, Inc.
Siu Stephen
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