Pharmacokinetic and pharmacodynamic relationships

Upon completion of this chapter, you will have the ability to  

It has been said that pharmacokinetics describes what the body does to the drug (absorption, distribution and elimination) while pharmacodynamics measures what the drug does to the body (therapeutic and/or toxic effect). The entire science of pharmacokinetics is predicated on the observation that, for most drugs, there is a correlation between drug response and drug concentration in the plasma. This correlation is not, however, a linear one. In fact, for most drugs, a sigmoidal (S-shaped) relationship exists between these two factors. 

In Fig. 17.1, the therapeutic effect reaches a plateau, where increase in drug concentration will have no further increase in effect. In contrast, the toxic effects of a drug show no such plateau. Toxic effects start at the minimum toxic concentration and continue to rise, without limit, as drug concentration increases (Fig. 17.2). 

Upon consideration, it is clear that the best measure of a dmg s activity at any given time would be obtained from a direct and quantitative measurement of the drug s therapeutic effect. This is, in 

Sigmoidal relationship between effect (forced expiratory volume in Is [FEVi]) and plasma drug concentration 

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Bhat, B. G., Hosea, N., Fanjul, A., Herrera, J., Chapman, J., Thalacker, F., Stewart, P. M., Rejto, P. A. (2008) Demonstration of proof of mechanism and pharmacokinetics and pharmacodynamic relationship with 4,-cyanobiphenyl-4-sulfonic acid(6-amino-pyridin-2-yl)amide (PF-915275), an... 

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. 

Fig. 10 Pharmacokinetic and pharmacodynamic relationship between cetrorelix (O) and LH concentrations (A) after single doses of 1, 3, and 5 mg cetrorelix in representative subjects. Left panel LH suppression. Right panel LH...

Figure 4 Pharmacokinetic and pharmacodynamic relationship of each warfarin enantiomer when 1 mg single warfarin enantiomer was administered to steady-state in five volunteers, followed by a short infusion of vitamin Kl. It is apparent that the S enantiomer is more efficient in preventing conversion of the inactive vitamin Kl epoxide to active vitamin Kl and increasing prothrombin time. (Plot constructed from data presented in Ref 290.)...

Fig. 21.3. Schematic diagram of the relationship between pharmacokinetics and pharmacodynamics in order to better understand the action of drugs.

To Study interactions between proteins and drugs, an available tool is the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) Associated Protein Database (see Table 1.5). The database contains information about relevant proteins, functions, similarities, substrates and hgands, tissue distributions, and other features of targets. Eor the understanding of pharmacokinetic (PK) and pharmacodynamic (PD) features, some available resources are listed in Table 1.5. For example, the Pharmacokinetic and Pharmacodynamic Resources site provides links to relevant software, courses, textbooks, and journals (see Note 5). For quantitative structure-activity relationship (QSAR), the QSAR Datasets site collects data sets that are available in a structural format (see Table 1.5). 

Comprehensive knowledge of the clinical pharmacology (e.g., concentration-effect relationships, pharmacokinetic and pharmacodynamic profile, information related to altered drug disposition and/or action consequent to development, disease, concomitant drug therapy) for the drug(s) of interest... 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are absorption, distribution, and elimination. 

Knowing the relationship between dose, drug concentration, and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles. 

Much has been published on the extrapolation of in vivo data from animals to humans. These include pharmacokinetic data (e.g. half-lives, plasma concentrations, clearances and rates of metabolism) and pharmacodynamic data (e.g. effective and toxic doses). Two excellent reviews present many examples and insightful discussions on isometric and allometric relationships, time scales, interspecies pharmacokinetic and pharmacodynamic scaling, and physiological models (Boxenbaum and D Souza, 1990 Chappell and Mordenti, 1991). 

Many time-dependent processes appear to be nonlinear, yet when the drug concentration is measured carefully relative to the time of dose, the underlying dose-to-drug-concentration relationship is directly proportional to the dose and therefore is linear (see Time- and State-Varying Pharmacokinetics and Pharmacodynamics ). 

PB-PK modelling allows further refinement of the dose-response evaluation by partitioning the relationship into pharmacokinetic (exposure vs. tissues dose) and pharmacodynamic (tissue dose vs. toxic response) components. This allows the uncertainties associated with each component to be assessed separately and adds accuracy to the overall animal to man extrapolation. Future developments of PB-PK modelling may allow specific sub-populations such as the newborn or individuals with metabolic variations to be taken into account. However, before this can be done there will need to be considerable growth in the amounts of physiological, pharmacokinetic and pharmacodynamic information available. 

Darwish M (1999) The relationship between the pharmacokinetics and pharmacodynamics of zaleplon. Eur Neuropsychopharmacol 5 (Suppl) S361... 

In general, the efficacy of hypnotics for short-term use is well established and there is a close relationship between their pharmacokinetic and pharmacodynamic profiles. The most widely used hypnotic in the UK, for example, is temazepam, which is relatively slowly absorbed and therefore has only a marginal effect on the sleep latency but facilitates sleep duration. 

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 ... 

Lundahl J, Regardh CG, Edgar B, et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol 1995 49(l-2) 61-67. 

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