Pharmacodynamics case studies

Meibohm B, editor. Pharmacokinetics and pharmacodynamics of biotech drugs principles and case studies in drug development. Weinheim (Germany) Wiley-VCH 2006. 

Although not perfect, Hansch s lipophilicity parameter and log P values are the most widely used parameters in QSAR studies. In addition to their effectiveness in predicting biological activity through target binding (pharmacodynamics), both parameters also affect pharmacokinetics. The pharmacokinetic applications of log P and 7r-values can be seen in Lipinski s rules and a Case Study (Carboxylate Antifungals) later in this chapter. 

In this chapter a number of approaches will be discussed that have been developed to address the challenges in macromolecule drag assays that impact upon selectivity, accuracy, and precision. The most commonly used methods for pro-tein/peptide drags - IA and LC-MS/MS - are discussed in detail, with case studies to illustrate the process, issues, assay approaches, and method limitations. Other less common methods and emerging technologies will be briefly mentioned. Biologic therapeutics that are not pure and/or not well characterized pose extra challenges which are beyond the scope of this chapter. Neither will biomarker assays used to support pharmacodynamic (PD) studies be covered in this chapter. 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

Pharmacodynamic (PD) studies are also performed to estimate the bioavailability and bioequivalence of drugs from topically applied semisolids. In this case, known therapeutic responses from drug products such as skin blanching due to vasoconstrictor effects caused by corticosteroids and transepidermal water loss caused by retinoids are measured and compared between the test and reference... 

In some instances (see example (e) in section 5.1, In vivo studies ) plasma concentration time-profile data are not suitable for assessing equivalence between two formulations. Although in some cases pharmacodynamic bioequivaience studies can be an appropriate tool for establishing equivalence, in others, this type of study cannot be performed because of a lack of meaningful pharmacodynamic parameters which can be measured a comparative clinical trial then has to be performed to demonstrate equivalence between... 

Meibohm B (2007). Pharmacokinetics and Pharmacodynamics of Biotech Dmgs Principles and Case Studies in Dmg Development. Wiley-VCH New York. 

The case studies will also consider situations where chemists have addressed the problem of irritancy to the gastrointestinal tract by making appropriate analogues. As a pharmaceutical chemist, because one will be able to relate the medicinal chemistry to the dmg s pharmacokinetics and pharmacodynamics, one will not only be able to understand why a patient needs a particular dmg, but what the best way to administrate it is, what dose and duration of action to expect (and why this is so), and why it elicits its effect. By understanding the medicinal chemistry of dmgs, from a pharmacokinetics perspective, one will be able to explain ... 

SMITH p (2008a), A cost-benefit analysis of the application of pharmacokinetic/ pharmacodynamic-based approaches to setting disc diffusion breakpoints in aquaculture a case study of oxolinic acid and Aeromonas salmonicida Aquaculture, 284,2-18. 

Although in many cases an enantiopure drug can be safer than the racemate, the advantages are clear. The final formulation of the drug product could be reduced inhalf, potential side effects could be minimized, and the resulting pharmokinetic and pharmacodynamic studies could clearly determine the efficacy of the active pharmaceutical ingredient (API) [21]. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Pharmacokinetics is closely related to pharmacodynamics, which is a recent development of great importance to the design of medicines. The former attempts to model and predict the amount of substance that can be expected at the target site at a certain time after administration. The latter studies the relationship between the amount delivered and the observable effect that follows. In some cases the observable effect can be related directly to the amount of drug delivered at the target site [2]. In many cases, however, this relationship is highly complex and requires extensive modeling and calculation. In this text we will mainly focus on the subject of pharmacokinetics which can be approached from two sides. The first approach is the classical one and is based on so-called compartmental models. It requires certain assumptions which will be explained later on. The second one is non-compartmental and avoids the assumptions of compartmental analysis. 

Obviously, if the clinical mirror approach to bioequivalency testing gains momentum, we may expect to see more quantification of clinical response in bioequivalency studies. In some instances pharmacodynamic parameters that are amenable to precise quantification are easily identified. Thus, if we are working with an antihypertensive drug, measurement of blood pressure using an electronic sphygnomanometer is an obvious option. However, for many drugs there is no simple way to quantify pharmacodynamic response. In some cases we may have to rely, to some extent at least, on patient diaries [41]. Such techniques are open to criticism of subjectivity and imprecision. 

Knowledge of which mechanism of delayed toxicity is operating in specific cases cannot usually be gained from the animal test or from epidemiology studies additional studies of ADME, and of pharmacodynamic interactions of the chemical with cellular components, are necessary to understand mechanisms of delayed toxicity. Some mechanisms are discussed in the following to illustrate the value of this kind of study. 

The Renwick work can be applied in the following way. Suppose it were possible in a specific case to develop a reasonably thorough picture of the comparative pharmacodynamic characteristics of a compound in humans and rats, and that the work revealed that no difference in pharmacodynamic response (at comparable doses) was expected. We would then turn to Table 9.1 and see that the typical pharmacodynamic difference between humans and animals (the default) puts humans at 2.5 times greater risk than animals. But now in our new case, the difference is seen to be a factor of 1.0 (no difference). We should be allowed to reduce the overall UF of 10 to a factor of 4.0, which is the default for pharmacokinetic differences (which we have not studied). Data substitute for defaults. Use of the Renwick defaults allows us to make some headway without having to take on... 

An additional consideration is the safety assessment of agents that will be used for challenge stimuli in the evaluation of pharmacodynamics. In some cases, there is a long history of uneventful clinical use of tests, for example, bronchial challenge with histamine and methacholine. If used in a similar manner, there may be no need to consider performing safety studies in... 

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