Concerning Pharmacokinetics and Pharmacodynamics

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Statistical Issues in Drug Development, 2nd Edition. Stephen Senn 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

Pharmacokinetics One of the magic arts of divination whereby needles are stuck into dummies in an attempt to predict profits. 

Few drugs are given Intravenously. This means that for most drugs the fraction which is absorbed intact into the circulation is often very much less than unity. This fraction, F, is referred to as the bioavailability. The bioavailability of oral formulations is often established in special studies (usually cross-over studies in healthy volunteers) in which the area under the plasma - concentration time curve (AUC) of the oral formulation is compared with that of an intravenous formulation. The bioavailability can then be calculated as the ratio of AUC to dose delivered for the oral formulation to the corresponding ratio for the intravenous formulation. Since the total amount eliminated from the body is equal to the clearance times the AUC, and since the total amount eliminated equals the amount absorbed, which is simply the dose times the bioavailability, so dose, AUC, bioavailability and clearance are linked by the formula, F x Dose = Clearance x AUC. For many drugs the bioavailability and clearance are independent of the dose administered. This property is referred to as dose-proportionality and is 

When plasma concentration, unbound concentration, the amount of drug and metabolite excreted and so forth all increase in proportion to dose, then the superposition principle applies. This means that concentration over time of a multidose treatment schedule can be calculated as the sum of the concentrations which would be observed from the individual doses were they given alone. For such drugs, the pharmacokinetics are said to be dose-independent or linear. Drugs which do not exhibit dose-proportionality can be difficult to manage. (A notorious example is alcohol.) 

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Pharmacokinetics and pharmacodynamics form the two major branches of pharmacoiogy. Pharmacokinetics is the study of drug disposition and deais with the processes of absorption, distribution, metaboiism and eiimination. Pharmacodynamics is concerned with the reiationship between the concentration of a drug and its effect. Put another way, pharmacodynamics is what a drug does to the body whiie pharmacokinetics is what the body does to a drug. This chapter wiii cover the generai principies reiating to these processes, and deveiop some of the principies that describe their kinetics and dynamics. 

As was noted in Chapter 4, pharmacokinetic and pharmacodynamic effects are studied in nonclinical research. These topics are also of critical importance in clinical investigations. A drug s pharmacokinetics and pharmacodynamics are of considerable interest to clinicians who may prescribe the drug to patients once it is approved. Meaningful decisions about a drug s optimal use can only be made with an understanding of the time course of events that occur after the drug s administration, and both pharmacokinetics and pharmacodynamics are concerned with this time course. By consideration of the pharmacokinetic processes of absorption, distribution, metabolism, and excretion (ADME), the... 

In both pharmacokinetic and pharmacodynamic considerations, an important emphasis concerns the rate at which events occur and the rate at which circumstances change. The pharmacokinetic phase covers the relationship between drug input and the concentration achieved over time. The pharmacodynamic phase covers the relationship between concentration and the therapeutic effect over time (toxicodynamics is concerned with the relationship between concentration and adverse effects over time). 

It was noted in the previous section that both pharmacokinetics and pharmacodynamics are concerned with relationships over time. One illustration of the fundamental importance of the rates of these processes can be seen in the plasma concentration-time profile (also known as the plasma-concentration curve) for an administered drug. This was introduced in Section 4.2.1, along with several quantitative pharmacokinetic terms used to describe and quantify aspects of the plasma concentration-time profile ... 

Beyond pharmacokinetics and pharmacodynamics, population modeling and parameter estimation are applications of a statistical model that has general validity, the nonlinear mixed effects model. The model has wide applicability in all areas, in the biomedical science and elsewhere, where a parametric functional relationship between some input and some response is studied and where random variability across individuals is of concern [458]. 

Once the health-effect endpoint and data points describing the exposure concentration-duration relationship have been selected, the values are plotted and fit to a mathematical equation from which the AEGL values are developed. There may be issues regarding the placement of the exponential function in the equation describing the concentration-duration relationship (e.g., C x t = k vs C X t = k2 vs X E = k3>. It is clear that the exposure concentration-duration relationship for a given chemical is directly related to its pharmacokinetic and pharmacodynamic properties. Hence, the use and proper placement of an exponent or exponents to describe these properties quantitatively is highly complex and not completely understood for all materials of concern. 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

Up to this point in our discussion of pharmacokinetics and pharmacodynamics, our discussion has emphasized the body s neurochemical changes in response to Its ingestion of chemical compounds we call drugs. This emphasis is consistent with the content and long history of the research that has been done on pharmacokinetics and pharmacodynamics. However, a more recently developed and much smaller area of research is concerned with possible ethnic and cultural differences in pharmacokinetics and pharmacodynamics (Lin Poland, 1995). 

Concerns relating to the inhibition of kinases known to phosphorylate tau relate to degree of inhibition. For any given kinase a balance is necessary. Thus, full inhibition of GSK-3 is probably not required to affect disease progression. Also, it is still unclear whether transient inhibition or sustained inhibition of GSK-3 is required to attenuate tau phosphorylation for an extended period of time. A detailed evaluation of the pharmacokinetic and pharmacodynamic relationship of a GSK-3 inhibitor coupled with biomarker endpoints could help contribute to overcoming similar issues. 

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