Precision potency

Compounds with cis double bonds in the side chain were in general found to be more potent and efficacious than their triple-bond congeners, both in in vivo and in in vitro functional assays [98, 106, 107]. QSAR models have been generated for the compounds with unsaturated [108] and l, l -dimethyl [96] side chains to determine more precisely the pharmacophoric requirements of the receptor. It is postulated that for optimum potency, the side chain must be of a suitable length and flexibility to have the ability to loop back so that its terminus is in proximity to the phenolic ring. The widely used, potency enhancing 1 - and 2 -methyl substituents would be expected to increase the tendency of the side chain to adopt a looped back, rather than an extended conformation. 

A number of oral solution or suspension products are included in the EPARs. Apart from the usual points of consideration for active ingredients and excipients, particular mention is made of possible precipitation of active ingredient when a solution is in use, the inclusion of excipients having a major impact on bioavailability, the need for flavoring to mask the taste of the active ingredient, relative potency compared with other routes of administration, preservation issues, dosing devices and the precision and accuracy of the dose delivered, and bioequivalence where formulations have been modified during the development process. 

In summary, results of in vivo experiments showed the effectiveness of carbosilane dendrimers having clustered Pk carbohydrate moieties, and the complete neutralization potency against STL-II was discovered when dumbbell-shaped dendrimers were identified as potent candidate inibitors. Although the precise mechanism of action remains to be elucidated, this type of inhibitor provided a new strategy for the detoxification of SLTs present in circulation. 

The Army, however, was now attempting for the first time to develop trustworthy estimates of how various doses of a given drug would affect populations, rather than single individuals. This required the establishment of parameters - numbers that would define the most probable quantitative clinical effects across a spectrum of subjects. Commanders would need to know not only the typical but also the probable range of response values for such important attributes as potency, time of onset, duration and other important aspects of drug action. Such precision is rarely called for in civilian settings (except in, e.g., cancer therapy). 

Of course, none of these data precisely establish the LD50, which is needed to estimate the therapeutic ratio (LD50/ID50). Nevertheless, extrapolation of the approximate therapeutic ratio for atropine (while also taking into account that lethality among the glycolates is proportional to their peripheral potency) provides the most feasible way to estimate the LD50 for the other belladonnoids (none of which have been known to have caused death in humans). 

At the beginning of the project, it is often difficult to have a precise idea of the projected therapeutic dose. Projects usually start with an estimated average potency of 1 mg/kg, once daily dose as an optimal approach. When initial pharmacokinetic/ pharmacodynamic (PK/PD) data becomes available one can better refine the TCP. Table 3.1 gives some guidelines on how to adjust the solubility requirement depending on the therapeutic dose and compound permeability. 

It is an essential condition of biological assay methods that the tests on the standard preparation and on the sample whose potency is being determined should be carried out at the same time and, in all other respects, under strictly comparable conditions. The validation of microbiological assay method includes performance criteria (analytical parameters) such as linearity, range, accuracy, precision, specificity, etc. 

All potency assays, from the simplest designs to the most complex Latin square design, necessitate potency estimation by computer. Low-precision assays employing plotting of zone sizes (response) against concentration of standards must be dealt with using computerized regression analysis, with the potency (standard equivalent) estimation calculated from the computed equation of the line. In this way, all opportunity for operator subjectivity is minimized. 

For low-precision design the statistical package should include statistical rejection of outlying or aberrant observation. (EP makes no provision for this USP has a test — USP 24, standard deviation, regression analysis, and potency estimation.)... 

The most important aspects of data handling for potency assays and low-precision assays are that the data is handled by validated computer programs and that the acceptance and rejection criteria incorporated are clear and based upon statistical or proven (at validation) limits. 

An example of the minimum requirement for potency assay of the drug substance and drug product is tabulated in Table 4. Note that the postponement of intermediate precision is aligned with previous discussion that the use of early phase analytical method resides mainly in one laboratory and is used only by a very limited number of analysts. Each individual company s phased method validation procedures and processes will vary, but the overall philosophy is the same. The extent of and expectations from early phase method validation are lower than the requirements in the later stages of development. The validation exercise becomes larger and more detailed and collects a larger body of data to ensure that the method is robust and appropriate for use at the commercial site. 

ICH Q2A suggested validation of the characteristics of accuracy, precision, specificity, linearity, and range for potency and content uniformity assay. A detailed discussion of each of these parameters is presented later in this chapter. Some examples of validation data are presented along with a brief critical discussion of the data. 

Reproducibility dosage strengths, the estimated intermediate precision is 0.9%. The average potency result... 

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