Predicted dose

Although the product has proven to be an effective (and relatively inexpensive) anticoagulant, it does suffer from a number of clinical disadvantages, including the need for a cofactor (antithrombin III) and poorly predictable dose responses. Despite such disadvantages, however, heparin still enjoys widespread clinical use. 

Human and animal evidence suggests there is a health risk for neurological effects only when exposures are high. There remains uncertainty in predicting dose levels for neurobehavioral effects, but 0.2 mg/kg body weight has been proposed as a threshold for convulsions in humans (Hayes 1963). 

Quantitative Stmcture-Activity Relationships (QSARs) are estimation methods developed and used in order to predict certain effects or properties of chemical substances, which are primarily based on the structure of the substance. They have been developed on the basis of experimental data on model substances. Quantitative predictions are usually in the form of a regression equation and would thus predict dose-response data as part of a QSAR assessment. QSAR models are available in the open literature for a wide range of endpoints, which are required for a hazard assessment, including several toxicological endpoints. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man. Toxicol Sci 118(2) 470 84... 

Ziprasidone s pharmacokinetics permit rapid and predictable dose adjustment, with metabolites that are considered to be clinically inactive ( 134). The results of PET pharmacokinetic and pharmacodynamic studies indicate that a twice daily dosage regimen is appropriate. 

Repeat steps 3-5, adjusting the predicted dose to achieve TC. 

After several years of study at Brookhaven National Laboratory analytical methods have been developed which we believe permit one to predict dose distribution in finite targets from finite sources with the required degree of accuracy. These methods and computer codes have been published (4). 

Profound hyponatremia due to reduced free water clearance is a predictable dose-related effect of vasopressin (17). This is a particular risk in patients who are unconscious or who have disturbed thirst sensation (SEDA-22, 487). 

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

The direct thrombin inhibitors have theoretical advantages over the indirect anticoagulants that include more predictable dose-responses, and efficacy against clot bound thrombin. With bivalirudin, clinical trials suggest superiority compared with heparin alone and comparable outcomes when... 

Ideally, DES polymers should have the characteristics listed in Table 2, namely, the ability to maintain mechanical integrity on stent expansion (i.e., it must not crack, flake, or delaminate) and to withstand sterilization. The polymer should demonstrate vascular compatibility in order to avoid inflammatory reactions, In addition, the polymer should enable consistent and predictable dosing and release kinetics (37). 

UK is nonantigenic and its mechanism of action is much more direct compared with that of streptokinase. UK cleaves plasminogen, by first-order reaction kinetics, to form plasmin. It is pH and temperature stable. The lack of circulating neutralizing antibodies and its direct mechanism of action allow for a predictable dose response relationship. 

Fig. 1.7 (a) Observed and model fitted percent responders in Phase II trials. (b)Predicted dose-response of response (% responders) in a Phase III population based on a population simulation of the Phase II model. The dotted lines are the 5th and 95th percentiles of the prediction distribution and represent uncertainty in the model parameters. 

Figure 4 Relative contribution by exposure route to predicted dose Estimated population lifetime average daily dose of arsenic for children exposed to chromated copper arsenate (CCA)-treated wood playsets and decks in warm climate regions (from Zartarian et al., 2006).

In the prediction of long-term "no effect" doses there are two important concepts to consider. One is that there are predictable dose relationships between acute, subchronic and chronic toxic effects. Acute toxicity tests refers to studies wherein single or repeated doses are studied 14 days or less. Subchronic (subacute) tests refers to studies wherein the doses are given five-seven days per week for 90 days, Subchronlc studies are also referred to as 13-week, three-month or short-term tests. 

Type A (Augmented) reactions will occur in everyone if enough of the drug is given because they are due to excess of normal, predictable, dose-related, pharmacodynamic effects. They are common and skilled management reduces their incidence, e.g. postural hypotension, hypoglycaemia, hypokalaemia. 

LMW heparins are less protein bound and have a predictable dose-response profile when administered s.c. or i.v. They also have a longer t/ than standard heparin preparations. 

Application of TK/PD modeling in predicting dose-limiting toxicity... 

The use of physiologically based pharmacokinetic models (PBPK) to translate applied dose in animal studies to predict dose and risk in humans is increasing. Many regulatory programs recommend use of PBPK modeling when data and information are adequate. 

AH of the equations previously described for predicting dose or concentration assume linear kinetic systems they are therefore not adaptable to treatment with drugs that display nonlinear kinetics. Using a linearized Michaelis-Menten equation, methods for predicting phenytoin dose and concentration have been developed and apphed to individual drug dosing regimens. 

---