Dose response comparative data

FIGURE 12.6 Measurement of full agonist affinity by the method of Furchgott. (a) Dose-response curve to oxotremorine obtained before (filled circles) and after (open circles) partial alkylation of the receptor population with controlled alkylation with phenoxybenzamine (10 jiM for 12 minutes followed by 60 minutes of wash). Real data for the curve after alkylation was compared to calculated concentrations from the fit control curve (see arrows), (b) Double reciprocal of equiactive concentrations of oxotremorine before (ordinates) and after (abscissae) alkylation according to Equation 5.12. The slope is linear with a slope of 609 and an intercept of 7.4 x 107 M-1. 

The next step was to augment and expand the model to be able to predict the dose response for the comparator. Comparator data, from SBA (summary basis for approval data submitted to the FDA), yielded one model that predicted both candidate and comparator performance. The model accounted for age, disease baseline, and trial differences. Differences based on sex, weight, and other covariates were estimated to be negligible. The addition of the comparator data improved the predictive ability of the model for both drugs (Fig. 22.3). 

Figure 22.3 The drug dose-response model was augmented by nsing data for the comparator drug. Because the mechanism of the drugs was the same, this comprised additional data for the model. This enhanced the predictive power of the model, in a better estimate for central tendency (solid line compared with dotted line) bnt also in smaller confidence intervals. This is especially prononnced at the higher doses— precisely where data on the drug were sparse. See color plate.

A complete dose-response analysis was generated for PCP for doses from 0.625 to 20 mg/kg IP (data not shown). PCP exhibited dose-related anticonvulsant action when day one minus day three differ ence scores were compared for all doses tested. When retested with saline only on day five, no reduction in convulsant sever it or super-sensitive response was observed (day one minus day five), indicating no carryover drug effect 48 hours after dosing. At behavioral ly equivalent doses, all compounds assayed were clearly anticonvulsant (table 3). TCP was most potent at the doses tested. PCA was the most efficacious, and reduced convulsant severity by 2.58 points. As with PCP, none of the other phencycli-noids had any carryover effects 48 hours after dosing (day one minus day five). 

Differences of opinion are common among epidemiologists based on what appears to be similar, if not comparable, data. In spite of the numerous large-scale and long-term investigations, the debate eontinues over whether there is a safe (threshold) level for asbestos or other fibrous materials, or if there is a linear dose-response relationship in the induction of cancer. Conclusions and interpretations of this body of data usually reflect personal philosophy and tolerance of risk. 

Sanner et al. (2001) have evaluated the proposed T25 method by comparing risk estimates obtained with this method to those obtained by using the LMS method (Section 6.3.1) as well as the LEDio method proposed by the US-EPA in 1996 (Section 6.3.2). The comparisons included both genotoxic and non-genotoxic carcinogens, as the main purpose was to compare the methods when the same data set was used, as well as to evaluate the possible effects of different shapes of the dose-response curves. 

Although testing of the whole mixture as such seems to be the proper way to approach the risk assessment of exposure to that mixture, it will not provide data on combined actions and/or interactions between the individual components of the mixture. Even if the effect of the mixture is compared with the effects of each individual component at comparable concentrations, this will not allow a description of potential synergism, potentiation, or antagonism, and it is even doubtful that deviations from additivity can be concluded. This can only be achieved if dose-response curves are obtained for each of the single compounds. 

Therapeutic Efficacy. The therapeutic efficacy of risperidone for schizophrenia has been well established in several controlled trials conducted worldwide ( 74, 75). The clinical efficacy trials performed to support approval of risperidone by regulatory agencies have all been published. Therefore, it is appropriate to combine these data using meta-analytic techniques to explore the efficacy of risperidone compared with neuroleptics. For most drugs, the relationship of dose and response is defined by the classic sigmoidal curve. Thus, as the dose (or plasma level) increases beyond a threshold and reaches the linear portion of the curve, response increases. Once the dose is high enough to produce maximal clinical response, the dose-response curve then levels off. 

Stadler IC, Karol MH. 1985. Use of dose-response data to compare the skin sensitizing abilities of dicyclohexylmethane-4,4 -diisocyanate and piciyl chloride in two animal species. Toxicol Appl Pharmacol... 

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