Dose prediction

FIGURE 7-4 Uptake or dose predicted for eadi model s ment by kfeJilton etal.fat gases of difiRsreiit sdubOities at 37 C. Tidal vcrfume SOO cm. Inspiration time 2 s. Nfodified from McJilton et al. 

Geller, B. and Fetner, H.H. (1989a) Children s 24-hour serum lithium level after a single dose predicts initial dose and steady-state plasma level [letter]. / Clin Psychopharmacol 9 155. 

Enns, N. and Karvelas, L. (1995) Electrical dose titration for electroconvulsive therapy a comparison with dose prediction methods. Convulsive Ther 11 86-93. 

Madakasira S, Preskorn SH, Weller R, et al. Single dose prediction of steady state plasma levels of amitriptyline. J Clin Psychopharmacol 1982 2 136-139. 

Because lithium has a half-life of approximately 24 hours and it takes four to five half-lives to achieve steady-state at a fixed dose, blood levels should be obtained every 5 days until an adequate therapeutic concentration is achieved or adverse effects preclude further increases. Attempts to develop dose prediction formulae to obtain therapeutic concentrations more rapidly have been promising, but they have not enjoyed widespread utilization ( 101, 102 and 103). While premature monitoring may lead to higher than necessary dosing, more frequent measuring of levels may be warranted in patients with known sensitivity to lithium or if... 

Markoff RA, King M Jr. Does lithium dose prediction improve treatment efficiency Prospective evaluation of a mathematical method. J Clin Psychopharmacol 1992 12 305-308. 

Purpose Pesticide registration Food and color IND/NDR Assessment and Select chronic dose Predict dose range for... 

Cheng40 reviewed in silico models of hepatotoxicity with the conclusion that no dose-prediction is in scope as today. However, continuing efforts, such as MCASE, based on postmarket adverse effect data41 will continuously enhance and ultimately improve in silico prediction of liver toxicity. 

Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007 5(I) 8 16. 

Koup JR, Killen T, Bauer LA. Multiple-dose nonlinear regression analysis program Aminoglycoside dose prediction. Chn Pharmacokinet 1983 8 456 62. 

The ingested doses predicted by the one-compartment and PBPK models, therefore, are also probability distributions that reflect the likelihood that any given ingested dose could give rise to the critical biomarker concentratioa... 

The right-hand side of Equation 1.30 also equals the accumulation factor, which is the factor by which accumulation occurs in the body upon multiple dosing, predicting the increase in relative to This factor can also be used to establish a... 

For workers on the site, the dose predictions should be based on the specific operations involved in the running and servicing of the plant. The dose predictions should include the contributions from direct radiation and from the intake of radioactive material. The analysis should take account of the duration, frequency and numbers of people involved in each of the activities. Estimates should be made of both the highest individual dose and the annual group average dose. 

For members of the public, the dose predictions should include the contributions from direct radiation, intake of radioactive material and doses received through the food chain as a result of discharges of radioactive material from the plant The doses should be estimated for the critical group. 

When there are uncertainties in making the dose predictions, conservative assumptions should be made. 

When the dose predictions depend on the dose rates arising from the buildup in the level of the inventories of radioactive material or from the level of contamination, the prediction should be based on the maximum values that are likely to occur during the lifetime of the plant. 

The dose predictions should take account of any relevant operating experience data. This could be derived from the operation of the actual plant or similar plants. 

Presentation of results of performance assessmoits This last issue to be raised concerns the increasingly important question of how to best present the results of a performance assessment. Different readers can react differently to the same presentation. The technical expert when confronted with yet another plot of time-dependent radioactivity releases will realise that time axes which extend up to 10 years or release rates down to Ifr Bq/y (both of which are actual examples from the literature ) are merely indicative of the numerical limits set on the computer run - but the uninitiated may conclude that we really believe oiuselves able to predict such nonsensical numbers. The nonexpert will be confused by complex, probabilistically expressed results the specialist will quickly ask the probabilities associated with purely deterministically treated scenarios. No one outside the radiation protection field will fidly grasp ihe (in)significance of extronely low dose predictions if a perspective of their health effects is not provided. 

Once a release has occurred such information should be retrieved as rapidly as possible and used in conjunction with meteorological data and dose prediction models to define the geographical areas of concern and to make prehminary estimates of the projected doses. It should always be understood, however, that further releases may have occurred owing to building leaks or at locations not designed for the discharge of radionuclides. 

Clearly, to be able to apply this approach in projects at an early stage, a validation is necessary that convinces the teams that this data will be useful. To this end, dose, C ax (maximum plasma concentration), and C ,i (minimum plasma concentration, at 12 h time point) data from a number of AZ CD compounds (22 compounds in total, comprising 4 acids, 6 bases, 11 neutrals, and 1 zwitterion) that have entered phase I clinical trials, usually across a number of dose levels, were collated. Human dose predictions (eD2M values) for this compound data set were also undertaken, using the models and inputs described above, while in vitro clearance was described by CLm, data determined in human hepatocytes. All clinically utilized human doses were then normalized in two ways. 

On the face of it, when fhalf of this compound is predicted to be >3 h, it is likely to be a CD (as its dose will be <70 mg). However, the predicted Thaif only has to decrease to about 2 h for the predicted dose to become unacceptably large (>500 mg), whereas if Thaif=6h, the predicted dose remains acceptable with a twofold reduction to 3 h. It looks like Thaif is indeed a parameter that can profoundly affect dose predictions, but is not in itself able to be optimized. However, closer inspection of the model shows that Thaif is a composite parameter ... 

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