Drug criteria

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

Often these design criteria involve competitive requirements. What is best for meeting one criterion may be counterproductive in meeting another. For example, certain excipients such as the hydrophobic stearate lubricants are important for efficient manufacture, yet they have the potential to retard the release of drug from an immediate-release formulation. The design of a dosage form thus frequently requires the optimization of formulation and process variables in a way that best meets all design criteria. 

Biological activity is not the only criterion required for drug development, as anyone who has been involved in this area is aware. Potency, toxicity, bioavailability, metabolic stability, and plasma half-life are only a few of the critical issues that must be addressed. Although satisfactory potency and spectrum activity had been achieved with WIN54954, which has been clinically evaluated, this compound lacked metabolic stability and consequently displayed a short half-life. 

The use of a membrane-limited two- or three-subcompartment organ model is indicated if tissue drug concentrations do not decline in parallel with drug concentrations in plasma or blood. A formal criterion has been given by Dedrick and Bischoff [10] such that if... 

The criteria used to fix the individual prices of drugs in each country that opts for this type of system are various the therapeutic value of new products, the cost of comparable treatment, the manufacturer s contribution to the national economy and the observed price in other countries. Table 3.2 shows a comparison of the use of these criteria in several OECD countries according to the answers given to a survey carried out in each country. As can be seen from the table, all the countries that responded to the survey acknowledge use of the comparison of authorized prices in other countries as a price-setting criterion. 

A compound can be classified as a high-solubility drug if the highest strength can be dissolved in 250 mL buffer at all pH values within the range of 1 to 8. This criterion is applied both by the European and US guidelines [17, 19]. 

The acceptance criterion for recovery data is 98-102% or 95-105% for drug preparations. In biological samples, the recovery should be 10%, and the range of the investigated concentrations is 20% of the target concentrations. For trace level analysis, the acceptance criteria are 70-120% (for below 1 ppm), 80-120% (for above 100 ppb), and 60-100% (for below 100 ppb) [2]. For impurities, the acceptance criteria are 20% (for impurity levels <0.5%) and 10% (for impurity levels >0.5%) [30], The AOAC (cited in Ref. [11]) described the recovery acceptance criteria at different concentrations, as detailed in Table 2. A statistically valid test, such as a /-test, the Doerffel-test, or the Wilcoxon-test, can be used to prove whether there is no significant difference between the result of accuracy study with the true value [29],... 

Predictive validity is the ability of a model to predict the effect that pharmacological or other manipulations will have on the condition being modeled. This criterion can present a real difficulty, in that drug development is often dictated by animal models. For example, if a given model only detects a subset of effective compounds (i.e. those belonging to a specific chemical class), then useful candidates will be discarded long before clinical trials, and the flaw in the model s predictive validity will not be discovered. Thus, the possibility that a model will yield false negatives cannot be ruled out. 

The information used for dose selection usually comes from subchronic toxicity studies, but other information about the pharmacological effects of a drug and its metabolism and pharmacokinetics may also be considered. The maximum recommended human dose (MRHD) of the drug may be an additional criterion, if this is known when the carcinogenicity studies are being designed. 

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