Drug quantitative assessment

Two issues present themselves when the question of PB-PK model validation is raised. The first issue is the accuracy with which the model predicts actual drug concentrations. The actual concentration-time data have most likely been used to estimate certain total parameters. Quantitative assessment, via goodness-of-fit tests, should be done to assess the accuracy of the model predictions. Too often, model acceptance is based on subjective evaluation of graphical comparisons of observed and predicted concentration values. 

Some idea of the rate of absorption can be obtained from examination of the plasma concentration-time profile. It should be remembered, however, that the time to maximum plasma concentration Y ) is not when absorption is complete but when the rates of drug absorption and elimination are equal. Thus two drugs with the same absorption rate will differ in /max if elimination rates differ. Assessment of the rate of absorption can also be confounded by complex or slow drug distribution. For example, the calcium-channel blocker amlodipine has a much later /max than other similar drugs. This is not due to slow absorption but to partitioning in the liver membrane with slow redistribution. A quantitative assessment of the rate of absorption can be obtained by deconvolution of plasma profiles following IV and oral administration. 

C.J. Bachmeier, T.J. Spitzenberger, W.F. Elmquist, and D.W. Miller. Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier. Pharm Res. 22 1259-1268 (2005). 

Christensen, H., Baker, M., Tucker, G.T. and Rostami-Hodjegan, A. (2006) Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data. Journal of Pharmaceutical Sciences, 95, 2778-2787. 

We statistically summarize drug outcome studies, producing a bottom-line quantitative assessment of the difference between an experimental drug and placebo or other standard agent (see Drug Management later in this chapter). 

Blanchard N et al Qualitative and quantitative assessment of drug-drug interaction potential in man, based on Ki, IC50 and inhibitor concentration. Curr Drug Metab 2004 5 147. [PMID 15078192]... 

Honeywell-Nguyen, P.L., G.S. Gooris, and J.A. Bouwstra. 2004. Quantitative assessment of the transport of elastic and rigid vesicle components and a model drug from these vesicle formulations into human skin in vivo. J Invest Dermatol 123 902. 

Quantitative assessment of the potency of a drug s effect on an isolated tissue, cell, animal or man. Computer-based science of logging and comparing DNA sequences. 

The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized ... 

Dapsone (4,4 -diaminodiphenylsulfone) has been widely used for phenotyping with respect to acetylation by NAT-2 however, the drug is also N-hydroxylated. Formation of the hydroxylamine metabolite by human liver microsomes was found to be selectively mediated by CYP3A (286) this led to the development of a zero- to eight-hour urinary metabolic recovery ratio approach [dapsone hydroxylamine (dapsone + dapsone hydroxylamine)] to quantitatively assess this pathway of metabolism (287,288). Subsequently, the trait measure has been applied as part of a cocktail approach (35) in a number of studies investigating the putative role of CYP3A as a risk factor in cancer (289-291) and other disease states (288,292,293). 

The binding constant between FITC-labeled bovine serum albumin and its monoclonal antibody was determined using ACE with LIF [14], Interaction of the enzyme cyclophilin with the immunosuppressive drug cyclosporine A was quantitatively assessed by CE with UV detection [15]. In the latter case the authors showed in particular how the difference between the sensitivity of the detector and KD of the studied system can severely hamper the correct determination of binding constants. 

Recent advances in mass spectrometry have rendered it an attractive and versatile tool in industrial and academic research laboratories. As a part of this rapid growth, a considerable body of hterature has been devoted to the apph-cation of mass spectrometry in clinical studies. In concert with separation techniques such as hquid chromatography, mass spectrometry allows the rapid characterization and quantitative determination of a large array of molecules in complex mixtures. Herein, we present an overview of the above techniques accompanied with several examples of the use of liquid chromatography-tandem mass spectrometry in pharmacokinetics/drug metabohsm assessment during drug development. 

Accuracy by Comparison. For drug substance, the only possibility of a quantitative assessment of accuracy is the comparison to the results of another analytical procedure or to a reference (if established with other procedures and/or additional characterization). This can be performed statistically with a r-test (see statistical textbooks or corresponding software). However, the shortcomings of these statistical tests (or better the justification of their use) are especially important here. It must be taken into consideration that two independent analytical procedures most probably differ in their specificity. This may lead to a systematic influence on the results (Table 2). If the effect can be quantified, the means should be corrected before performing the statistical comparison. If a... 

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