Pharmacokinetics predictive value

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

The pharmacokinetics of a drug in rodents, dogs and primates are certainly of some predictive value to humans, although there can often be surprises. If there is good agreement between species, it is likely that humans will handle the drug in a similar fashion. Conversely, if the major clearance mechanism, metabolic or... 

The commonsense approach to the interpretation of drug concentrations compares predictions of pharmacokinetic parameters and expected concentrations to measured values. If measured concentrations differ by more than 20% from predicted values, revised estimates of Vd or CL for that patient should be calculated using equation (1) or equation (2). If the change calculated is more than a 100% increase or 50% decrease in either Vd or CL, the assumptions made about the timing of the sample and the dosing history should be critically examined. 

Biopharmaceuticals represent a broad but discrete class of large molecular weight therapeutic entities that are characterized by their specific pharmacological activities and distinctive pharmacokinetics. The selection of an appropriate animal model is dependent on a combination of PD and PK factors. As described in this chapter, it is essential to understand the relationship of the basic pharmacology of a biopharmaceutical (signaling, receptor presence, binding properties, etc.) and the associated PK properties to that expected in humans, in order to select animal species that will have the most predictive value in safety assessments. 

Pharmacokinetic studies in reproductive and developmental toxicology are most useful if they are conducted in animals during the stages in which reproductive and developmental insults occur. The correlation of pharmacokinetic parameters and reproductive and developmental toxicity data might enhance our understanding of both the effects observed and of their predictive value (Kimmel and Young 1983 Hansen et al. 1999). 

Sheiner and Beal (1981) have pointed out the errors involved in using the correlation coefficient to assess the goodness of fit (GOF) in pharmacokinetic models. Pearson s correlation coefficient overestimates the predictability of the model because it represents the best linear line between two variables. A more appropriate estimator would be a measure of the deviation from the line of unity because if a model perfectly predicts the observed data then all the predicted values should be equal to all the observed values and a scatter plot of observed vs. predicted values should form a straight line whose origin is at the point (0,0) and whose slope is equal to a 45° line. Any deviation from this line represents both random and systemic error. 

Now suppose data were available only in animal species and it was of interest to predict the pharmacokinetics of relaxin in humans. Fitting Eq. (5.2) to only the animal data gives, Ln(0i) = 1.763 0.155, 02 = 0.776 0.0680, and coefficient of determination of 0.9849. Overall, the precision of the model was slightly less than the previous one. The predicted value for a 62.4 kg adult female is then... 

Disposition and Pharmacokinetics Azathioprine is well absorbed orally and reaches maximum blood levels within 1-2 hours after administration. The tj of azathioprine is 10 minutes, while that of its metabohte 6-mercaptopurine is about an hour. Blood levels have limited predictive value because of extensive metabolism, significant activity of many different metabolites, and high tissue levels attained. Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. Both are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance has little impact on biological effectiveness or toxicity, but the dose should be reduced in patients with renal failure. 

The validity of the animal data addresses not only the accuracy of the findings but also the relevance of the experimental data for man. If comparative metabolic or pharmacokinetic studies reveal a quantitative difference between the test animal and human responses or routes of exposure, the findings may totally lack predictive value. Such studies are rarely performed because of the limitations imposed by time and funding thus there is usually no alternative but to err on the side of prudence and accept positive animal findings. Unless there is evidence to the contrary, a regulator has no choice but to assume that test animal data may be predictive of the response among at least some individuals in the heterogeneous human population. 

What are the strengths and weaknesses of these approaches The use of intrinsic clearance in vitro permits predictions between species for the particular enzyme/route of metabolism concerned. If humans have qualitatively different routes of metabolism for any particular compound, then this will weaken the predictive value of the in vitro observation. Similarly, allometric scaling works best for compounds with a high component of non-enzymatic elimination, such as our model compound with approximately 90% excretion as unchanged drug. This prediction weakens as variations in rates of enzymatic reactions become more important. The pharmacokinetic-pharmacodynamic modelling approaches use existing in vivo data to calculate constants which can be applied to other in vivo data, but does not, in its present form, link in vitro and in vivo data. 

In addition, non-pharmacokinetic statistical modeling approaches have been recommended to guide the dose escalation. These statistical approaches model the dose-toxicity relationship as a sigmoidal curve to predict the MTD. The predicted value of the MTD is adjusted as data on the occurrence or the absence of toxicity accumulate from the clinical trial. Thus, the statistical prediction of the MTD is higher when low toxicity is observed, allowing rapid dose escalation, and the predicted MTD is low when dose-related toxicity is observed, calling for conservative dose escalation steps. This approach of dose escalation has been termed the continual reassessment method (CRM) [54]. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

A recent variation on the prediction of human VD using allometric scaling involves the use of what has been termed "fractal volume of distribution (vf) [7], This refers to the VD value corrected to within the bounds of actual volumes within the body - in the case of human the upper and lower bounds would be 70 1 and plasma volume, respectively. Thus, even if a compound were to have a VDSS of 1000 1, its Vf would be 69.8 1. The authors of this approach have shown that Vf scales allometrically across species better than VD [8], with the explanation that body volume and body mass are exactly scaleable across species. Animal values for Vf are calculated from VD obtained from pharmacokinetic studies using the relationship ... 

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