Potency index

In order to express the carcinogenic response or potency, a dose descriptor is used, for example the Tumorigenic Dose (TD). The TD is often set at a defined incidence, for example 5%, the TD5, defined as the dose (or concentration) associated with a 5% incidence of mmors. The dose descriptor can serve as the basis for development of an Exposure/Potency Index (EPl), which is the estimated daily human exposure divided by the TD. A calculated EPl of 10 for the TD5 represents a one million-fold difference between the human exposure and that at the lower end of the dose-response curve, on which the estimate of potency is based. 

The T25 was originally proposed as a simplihed carcinogenic potency index as a practical method for potency considerations in carcinogen classihcation systems (Dybing et al. 1997) and is used within the EU context of classihcation and labeling of chemical substances (see Section 2.4.1.8) for inclusion of potency considerations in setting specihc concentration limits for carcinogens in Annex I of Directive 67/548/EEC (EC 1999). 

Dybing, E., T. Sanner, H. Roelfzema, K. Kroese, and R.W. Tennant. 1997. T25 A simplified carcinogenic potency index Description of the system and study of correlations between carcinogenic potency and species/site specificity and mutagenicity. Pharmacol. Toxicol. 80 272-279. 

Induction of CYP expression by xenobiotics has been reported in mainly three ways (1) induction potential (fold induction over control), (2) EC50 (effective concentration for 50% maximal induction), and (3) potency index (the ratio of induction response of the test compound compared to that of a gold standard). In our laboratory, we have defined CYP induction as a potency index or a percentage of a classic inducer rather than as fold increase over a control (induction potential). The reason for this is twofold. First, the basal levels of some CYPs may be low and therefore difficult to accurately quantitate. Second, we, and others, have found that basal CYP levels in culture may be highly... 

Figure 5 In vitro versus in vivo induction of CYP2B (A) and CYP3A (B). Cultured rat hepatocytes and Sprague Dawley rats were treated with 13 drug candidates at a dose of 50 pM and 400 mg/kg, respectively. Potency indexes for all the compounds in vitro were compared to ones found in vivo. Source From Ref. 12.

Ball, C. McGonagle, M. P. (1987) Development and evaluation of a potency index screen for detecting mutants of Penicillium chrysogenum having increased penicillin yield. J. Appl. Bacterial. 45,61-1 A. 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

This leads to the concept of therapeutic index. The potency of a drug is almost irrelevant. It is its specificity that matters. Thus if two drugs A and B are effective at the same dose in a patient, say 1 mg, but A produces toxic effects at 10 mg which are only seen with 500 mg of B then B is clearly a much safer drug than A, in that patient. The ratio of toxic to effective dose is the therapeutic index (TI). It is often expressed as... 

With tso as an index of carcinogenicity, an interspecies relative potency (IRP) can be defined, e.g.,... 

E I is a kinetic chimera Kj and kt are the constants characterizing the inactivation process kt is the first-order rate constant for inactivation at infinite inhibitor concentration and K, is the counterpart of the Michaelis constant. The k,/K, ratio is an index of the inhibitory potency. The parameters K, and k, are determined by analyzing the data obtained by using the incubation method or the progress curve method. In the incubation method, the pseudo-first-order constants /cobs are determined from the slopes of the semilogarithmic plots of remaining enzyme activity... 

Fabro, S., Shull, G. and Brown, N.A. (1982). The relative teratogenic index and teratogenic potency Proposed components of developmental toxicity risk assessment. Teratog. Carci-... 

The test method is based on the fact that sensitizers induce a proliferation of lymphocytes in the lymph node draining the site of substance administration. The increased proliferation is proportional to the applied dose of the chemical and the potency of the allergen. Hence, the murine LLNA assesses proliferation in a dose-response manner, comparing it to the proliferation in a control group. The ratio of the proliferation after sensitizer application to the control group defines the Stimulation Index (SI). 

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