Dose-response relationships parameters

Ohmori S, Harada K, Miura H. 1986b. Behavior of biological parameters for lead exposure in Japanese male workers II. Dose-response relationships between Pb-B and the parameters. Kumamoto Med J 39 201-229. 

The duration of repeat-dose studies should be at least as long as the proposed clinical study. These studies are designed to establish a dose-response relationship, define target organ(s) of toxicity, and determine whether observed toxicities are reversible. Evaluation parameters should include not only those routinely performed in the acute studies, but those performed in the additional studies as well. Special tests, such as ophthalmoscopic, electrocardiograph, body temperature, and blood... 

Another difference from drug therapy is that the dosing interval of a nutritional supplement is often not a critical parameter for a positive outcome. This lack of a strong dose-response relationship is an important consideration in setting of standards for dietary supplements and is in stark contrast to the situation for drug products. 

There are severai pharmacokinetic parameters that are reievant to the ciinicai use of drugs. These heip quantify a dose-response relationship, or... 

The linear component of the LMS model, qi (i.e., one of the parameters of the polynomial), is approximately equivalent to the slope at low doses of the dose-response relationship between the tumor incidence and the dose. This linearity at low dose is a property of the formulation developed for the multistage model and is considered by proponents to be one of its important properties. This linear component of the polynomial, qi, is used to carry out low-dose extrapolation. The linear response at low doses is considered to be conservative with regard to risk, as the dose-response relationship at low doses may well be sublinear. Although supralinearity at low doses cannot be excluded, it is usually considered to be unlikely. 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

It is natural to consider one or another of these trans-species dose prescriptions for scaling dose-response relationships in carcinogenesis. But in any chronic effect, such as carcinogenesis, another parameter enters namely, time. Whereas the LDjo describes the acutely toxic properties of a chemical, the relevant dose for carcinogenesis is usually accumulated over a long time. One must consider, therefore, the relationship between daily dose, total lifetime dose, and body weight. The difference in life spans between man and mouse—70 years versus 2 years—amounts to a factor 35. Most analyses, however, consider that it is the daily dose that is more relevant, and that the shorter lifetime of the mouse represents the effects of its higher metabolic rate. The difference between these various interspecies dose conversion schemes is illustrated in Thble 8.1. 

Anderson ME, Barton HA. 1998. The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure. Environ Hlth Perspect 106 Suppl. 1 349-356. 

Fig. 1.5 Illustration of the simulation and analysis of a virtual trial outcome. The solid line represent the true dose-response relationship based on a sampled set of parameters from the joint posterior distribution of the model parameters. The circles represent the simulated drug effects in the patients included in the trial on the basis of the true" model parameters and the errors bars...

Pharmacokinetics (PK) can be a major source of variability in the dose response relationship. It manifests itself in interindividual differences in the plasma concentration-time profile of a drug. Factors which lead to variability in the ADME parameters are therefore of importance in understanding overall variability in PK. 

Exposures of newborns to PAHs depend on pharmacokinetic processes operating in the mother, and transfer through breast milk. Since it is difficult to characterize these pathways in humans, physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) models need to be developed using appropriate animal models, and incorporating key parameters such as dose, exposure duration, and developmental stage (Dorman et al, 2001). Thus, development of PBPK and PBPD models for PAHs is an immediate need that will help in not only characterizing the dose-response relationship, but also extrapolation of results from animal studies to humans. 

Another method of detecting a dose-response relationship is to fit the data to various models for dose-response curves. This method statistically determines whether or not a dose-response model (such as a Logistic function) fits the data points more accurately than simply the mean of the values this method is described fully in Chapter 12. The most simple model would be to assume no dose-response relationship and calculate the mean of the ordinate data as the response for each concentration of ligand (horizontal straight line parallel to the abscissal axis). A more complex model would be to fit the data to a sigmoidal dose-response function (Equation 11.2). A sum of squares can be calculated for the simple model (response — mean of all response) and then for a fit of the data set refit to the four parameter Logistic shown... 

The parameters are eo (baseline response), Emax (maximum response), and ed50 (the dose that achieves 50% of maximum drug effect). Npuff is the number of puffs. In addition, it is assumed that the active ingredient in the test drug will be proportional to that of the reference drug, with a multiplication factor F. Under this assumption, the dose-response relationship for both the test and the reference drug can be written jointly as follows ... 

Given a postulated functional form of the dose-response relationship, the frequency of occurrence of toxic effects may be used to estimate the unknown parameters. tn addition, this estimated dose-response can be extrapolated to provide either (1) estimates of risk probabilities at lower dose levels, or (2) an estimate of the dose level associated with any particular probability of risk. Implicitly, this approach presumes that the true dose-response can be realized within the postulated functional form used in the estimation and extrapolation procedure. Although this presumption is often not critical for interpolation within the range of observed response rates, it may be extremely critical for extrapolation outside this observable range. 

An understanding of metabolism and kinetics is pertinent to the overall goal of this Symposium, inasmuch as the rate and pathway of the biotransformations in a given species are important determinants of the dose-response relationship of the therapeutic agent and its elimination kinetics and terminal residues. Clearly, the current literature reveals that biotransformation reactions play a role in the overall behavior of chemicals and drugs in aquatic species and that the manipulation of the rates of these reactions by inducers or inhibitors of biotransformation can significantly affect important kinetic and therapeutic parameters, such as steady-state tissue levels, persistence, and metabolite profiles. 

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