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Development & Regulation of Drugs ¾ Barry A. Berkowitz, PhD

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INTRODUCTION

New drugs have revolutionized the practice of medicine, converting many once fatal or debilitating diseases into manageable therapeutic exercises. For example, deaths from cardiovascular disease, the main cause of death in the USA, and from stroke have decreased by more than 50% in the USA over the past 30 years. This decline is due¾in part¾to the discovery and increased use of antihypertensives, cholesterol synthesis inhibitors, drugs that prevent or dissolve blood clots, medical devices, and drug-releasing stents.

Among the first steps in the development of a new drug is the discovery or synthesis of a potential new drug molecule and seeking an understanding of its interaction (mechanism) with the appropriate biologic targets. Repeated application of this approach leads to compounds with increased potency and selectivity (Figure 5-1). By law, the safety and efficacy of drugs must be defined before marketing. In addition to in vitro studies, relevant biologic effects, drug metabolism, and pharmacokinetic profiles and particularly an assessment of the relative safety of the drug must be characterized in animals before human drug trials can be started. With regulatory approval, human testing can then go forward in three phases before the drug can be considered for approval for general use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for general use.

Enormous and increasing costs, with estimates from $150 million to $900 million, are involved in the research and development of a single new drug that reaches the marketplace. Only 3 of 10 marketed drugs return their research and development (R&D) investments, thus providing considerable motivation to develop "blockbusters." Thousands of compounds may be synthesized and hundreds of thousands tested from libraries of compounds for each successful new drug lead, which then generally needs to be further optimized for reasons of potency, selectivity, drug metabolism, and dosing convenience before each drug reaches the market. Because of the economic investment required and the need to efficiently access multiple technologies, most new drugs are developed in pharmaceutical companies.

At the same time, the incentives to succeed in drug development can be equally enormous. The global market for pharmaceuticals in 2006 is estimated at about $640 billion. The 2004 sales of the top-selling drug worldwide (Lipitor) exceeded $10 billion. During the second half of the 20th century, estimates indicate that medications produced by the pharmaceutical industry saved more than 1.5 million lives and $140 billion in the costs of treatment for tuberculosis, poliomyelitis, coronary artery disease, and cerebrovascular disease alone. New drugs played a key role in the post-1995 decline in HIV mortality and the social returns for HIV drug innovation appear to be extremely large. In the USA, approximately 10% of the health care dollar is presently spent on prescription drugs.

 Figure 5-1. The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-threatening diseases. 0 

DRUG DISCOVERY

Introduction

Most new drugs or drug products are discovered or developed through one or more of six approaches:

1.    Identification or elucidation of a new drug target
2.    Rational drug design of a new drug based on an understanding of biologic mechanisms, drug receptor structure, and drug structure
3.    Chemical modification of a known molecule
4.    Screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, and large libraries of peptides, nucleic acids, and other organic molecules
5.    Biotechnology and cloning using genes to produce peptides and proteins. Efforts continue to focus on the discovery of new targets and approaches, from studies with genomics, proteomics, nucleic acids and molecular pharmacology for drug therapy. Significantly increasing the number of useful disease targets should be a positive driver for new and improved drugs.
6.    Combinations of known drugs to obtain additive or synergistic effects or a repositioning of a known drug for a new therapeutic use.

Drug Screening

Regardless of the source or the key idea leading to a drug candidate molecule, testing it involves a sequence of iterative experimentation and characterization called drug screening. A variety of biologic assays at the molecular, cellular, organ system, and whole animal levels are used to define the activity and selectivity of the drug (Table 5-1). The type and number of initial screening tests depend on the pharmacologic and therapeutic goal. Anti-infective drugs may be tested against a variety of infectious organisms some of which are resistant to standard agents, hypoglycemic drugs for their ability to lower blood sugar, etc. In addition, the molecule will also be studied for a broad array of other actions to establish the mechanism of action and selectivity of the drug. This has the advantage of demonstrating both suspected and unsuspected toxic effects. Occasionally, an unsuspected therapeutic action is serendipitously discovered by the careful observer. The selection of molecules for further study is most efficiently conducted in animal models of human disease. Where good predictive preclinical models exist (eg, antibacterials, hypertension or thrombotic disease), we generally have adequate drugs. Good drugs or break-though improvements are conspicuously lacking and slow for diseases for which pre-clinical models are poor, or not yet available, eg, Alzheimer's disease.

Studies are performed during drug screening to define the pharmacologic profile of the drug at the molecular, cellular, system, organ, and organism levels. For example, a broad range of tests would be performed on a drug designed to act as an antagonist at vascular a-adrenoceptors for the treatment of hypertension.

At the molecular level, the compound would be screened for receptor binding affinity to cell membranes containing a receptors (if possible on human receptors), other receptors, and binding sites on enzymes. If crystal structures of the drug and target are available, structural biology analyses or computer-assisted virtual screening might be done to better understand the drug receptor interaction. Early studies would be done to predict effects that might later cause undesired drug metabolism or toxicologic complications. For example, studies on liver cytochrome P450 enzymes would be performed to determine whether the drug of interest is likely to be a substrate or inhibitor of these enzymes or to interfere with the metabolism of other drugs. Effects on cardiac ion channels such as the hERG potassium channel, possibly predictive of life threatening arrhythmias, would be considered.

Effects on cell function would be studied to determine whether the drug is an agonist, partial agonist, or antagonist at a receptors. Isolated tissues, especially vascular smooth muscle, would be utilized to characterize the pharmacologic activity and selectivity of the new compound in comparison with reference compounds. Comparison with other drugs would also be undertaken in other in vitro preparations such as gastrointestinal and bronchial smooth muscle. At each step in this process, the compound would have to meet specific performance criteria to be carried further.

Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of all new drugs are generally first performed in normal animals. Where appropriate, studies on disease models would be performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see if blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy following oral and parenteral administration. If the agent possessed useful activity, it would be further studied for possible adverse effects on other major organ systems, including the respiratory, gastrointestinal, endocrine, and central nervous systems.

These studies might suggest the need for further chemical modification to achieve more desirable pharmacokinetic or pharmacodynamic properties. For example, oral administration studies might show that the drug was poorly absorbed or rapidly metabolized in the liver; modification to improve bioavailability might be indicated. If the drug was to be administered long-term, an assessment of tolerance development would be made. For drugs related to or having mechanisms of action similar to those known to cause physical dependence, abuse potential would also be studied. For each major action found, a pharmacologic mechanism would be sought.

The desired result of this screening procedure (which may have to be repeated several times with analogs or congeners of the original molecules) is called a lead compound, ie, a leading candidate for a successful new drug. A patent application would generally be filed for a novel compound (a composition of matter patent) that is efficacious, or for a new and nonobvious therapeutic use (a use patent) for a previously known chemical entity.

PRECLINICAL SAFETY & TOXICITY TESTING

All drugs are toxic at some dose. Seeking to correctly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug might be argued as the most essential part of the new drug development process. Most drug candidates fail to reach the market, but the art of drug discovery and development is the effective assessment and management of risk and not total risk avoidance.

Candidate drugs that survive the initial screening and profiling procedures must be carefully evaluated for potential risks before and during clinical testing. Depending on the proposed use of the drug, preclinical toxicity testing includes most or all of the procedures shown in Table 5-2. Although no chemical can be certified as completely "safe" (free of risk), the objective is to estimate the risk associated with exposure to the drug candidate and to consider this in the context of therapeutic needs and duration of likely drug use.

The goals of preclinical toxicity studies include identifying potential human toxicities; designing tests to further define the toxic mechanisms; and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Tables 5-1 and 5-2, several quantitative estimates are desirable. These include the "no-effect" dose¾the maximum dose at which a specified toxic effect is not seen; the minimum lethal dose¾the smallest dose that is observed to kill any experimental animal; and, if necessary, the median lethal dose (LD50)¾the dose that kills approximately 50% of the animals. Presently, the LD50 is estimated from the smallest number of animals possible. These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals.

It is important to recognize the limitations of preclinical testing. These include the following:

1.    Toxicity testing is time-consuming and expensive. Two to 6 years may be required to collect and analyze data on toxicity and estimates of therapeutic index (a comparison of the amount that causes the desired therapeutic effect to the amount that causes toxic effects, see Chapter 2) before the drug can be considered ready for testing in humans.
2.    Large numbers of animals may be needed to obtain valid preclinical data. Scientists are properly concerned about this situation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tissue culture in vitro methods are increasingly being used, but their predictive value is still severely limited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary.

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