Prediction of clinical effect

PREDICTION OF CLINICAL EFFECTS FROM PHARMACOLOGICAL DATA... 

The prediction of clinical effects from pharmacological data is the Holy Grail of many pharmacologists. But because pharmacological data can be obtained from biological systems at different levels of complexity, there are a number of rungs in the ladder of extrapolation to clinical effects. And how, the reader may wonder, is this pursuit relevant to the context of our discussion on complexity and emergent properties ... 

As illustrated above, analytical reasoning dominates current clinical pharmacology in that many efforts are directed at isolating and understanding the various factors that influence clinical effects. This is indeed the analytical phase outlined above, the indispensable phase of data gathering. But the objective is the prediction of clinical effects from results obtained with experimental model systems, and to this end a synthetic phase is necessary. 

One approach to formulating potential differences in ethnic response is to examine the metabolic pathways of the common antipsychotics and determine whether the known ethnic variations in metabolizing enzymes or other effects on absorption, distribution, and excretion can be applied a priori to predict potential clinical effects. In this section we will consider some of the commonly prescribed SGAs, and only briefly touch on the FGAs. 

Data from repeat-dose toxicity studies are essential for CTAs in the early stages of development of a compound, but are superseded once there is a reasonable amount of human data. Any target organs that are identified in the toxicity studies should be monitored in clinical trials. Definitive data on the effects derived from clinical trials will show whether the animal studies are predictive of the effects in humans. This information can then be used to help interpret findings in reproductive toxicity studies, such as whether general toxicity in the adult is relevant. If adult toxicity in animals is deemed relevant, the exposure at which it occurs can be used to estimate the clinical relevance of any reproductive effects. If toxic effects in animals are induced at exposures greatly in excess of the clinical exposure, then they might not be clinically relevant. 

Klein DF. Importance of psychiatric diagnosis in the prediction of clinical drug effects. Arch Gen Psychiatry 1967 16 118-126. 

The clinical relevance of data obtained from studies with single compounds is questionable, because most studies were performed in in vitro systems, limiting the predictability of the effects of the examined compounds in vivo. Moreover, some polyphenolics, such as quercetin, were shown to interact with the absorption or metabolism of drugs only at very high concentrations (50-100 pmol/L), which are likely to exceed the expected in vivo concentration after the consumption of a moderate amount of a grapefruit/ citrus product. Also, flavonoids have been demonstrated to potentially induce apoptosis in cell lines at concentrations comparable to those used for some in vitro drug interaction studies (64-66). This potentially could have impaired the investigation of enzyme and transporter activities. 

Kraiczi, H., Frisen, M. Effect of uncertainty about population parameters on pharmacodynamics-based prediction of clinical trial power. Contemp Clin Trials 2005, 26 118-130. 

Many animal models use infections artificially introduced into the animal either systemically or into specific organs or tissues. The behavior of infections and the efficacy of antibiotics in eliminating those infections differ, depending on the organ or tissue involved. The type of local pathology, the penetration and pharmacokinetics of antibiotics, the local host defense system, and the clearance rates for the bacterial inocula differ among the various organs and tissues of an animal. Therefore, to get a reliable prediction of how effective an antibiotic will be clinically it is... 

Greenwood D. Antibiotic effects in vitro and the prediction of clinical response. J Antimicrob Chemother 1997 40 499-501. 

Predict the clinical effect of an obstrnction in the bile duct. 

Since the threshold concentration will vary among patients, the probability of the effect to be present at a certain concentration will be a function of the threshold concentration distribution in the population. This approach may be useful in the clinical setting as an approximation of dose-response relationships but has major limitations for the prediction of complete effect-time profiles. ... 

The effects shown by contacting the foreign surface in the coagulation of blood have been further complicated by the use of the kinds of polymers in some investigations with resultant scattering of data ". In addition, we studied the functional effects of exposure of blood coagulation factors and platelets to the surfaces of synthetic polymers from the viewpoint that extrapolation from the behaviors in vitro to their antithrombogenic behaviors in vivo would allow prediction of clinical usefulness of candidate materials. /... 

While the charcoal meal method has been shown to be relatively predictive of GI effects in the clinic (Redfem et al. 2010), the information obtained is limited (gastric emptying and small intestinal transit data only). Moreover, it is a terminal method which requires fasting prior to dosing. This makes it unsuitable to use as an additional endpoint in toxicology studies and sits best as a stand-alone SP study. 

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