Pharmacokinetics and pharmacodynamics variability

D. J. Kopacz, C. M. Bernards, H. W. Allen, C. Landau, P. Nandy, D. Wu, and P. G. Lacouture. A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans Bupivacaine-loaded microcapsules. Anaesth. Analg. 97 124-131 (2003). 

Piotrovsky, V. Pharmacokinetic and pharmacodynamic variability estimation and appraisal of its impact on dose optimization with an example of gender differences. In Krishna, R., ed. Dose optimization in drug development. (Drugs and the... 

Identifying safer drugs, especially the ability to predict which drug is more likely to be safe in a realistic clinical setting with divergent pharmacokinetic and pharmacodynamic variables, is a key strategy toward minimizing DILL As with... 

Suzuki A, Suzuki M, Yamamoto Y, Tremaine L (2012) Impact of drug transporter pharma-cogenomics on pharmacokinetic and pharmacodynamic variability—considerations for drug development. Expert Opin Drug Metab Toxicol 8 723-743. doi 10.1517/17425255.2 012.678048... 

A therapeutic failure with one opioid agonist does not necessarily mean that the patient will fail to respond to others. Pharmacokinetic and pharmacodynamic variabilities as well as genetic polymorphisms in mu opioid receptors are known to influence opioid dose response. These inter-individual variations are respon-... 

Geriatric factors a variety of factors, both pharmacokinetic and pharmacodynamic, that contribute to variable dmg responses in the elderly. These responses are not seen for every class of dmg. Thus, the depressant effects of the glycosides also appear to increase with aging (116,117). 

It is widely held that differences exist in the usage and dosage of antipsychotics among ethnic minority groups. A number of factors are felt to account for these differences and include sociocultural variables (racial bias, cultural divide between patient and physician, language), as well as biological variables (pharmacogenetic, pharmacokinetic, and pharmacodynamic). 

Fig. 14. Schematic description of pharmacokinetic and pharmacodynamic determinants of drug action. Distribution from the measurement site (Cp) to the biophase (Ce), determined by a distribution rate constant is followed by drug-induced inhibition or stimulation of the production (k ) or removal (A out) of a mediator (R), transduction of the response R and further transformation of R to the measured effect E, if the measured effect variable is not R. (Modified from Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6.)...

Even in people with the same diagnosis and the same inclusion and exclusion criteria, there are different treatment responses based on individual variability. The most important individual variables are probably sex and age. It is unfortunate that even though affective disorders and some anxiety disorders are more prevalent in women than in men, until recently results of clinical trials did not take into consideration sex differences and variables unique to women [e.g., reproductive status and menstrual cycle]. As is demonstrated by Yonkers et al. [see Chapter 5, in this volume], there are substantial sex differences in the pharmacokinetics and pharmacodynamics of most antidepressants and anxiolytics, which influence treatment response. Attention to these variables will indeed improve the efficacy of treatment. 

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 mechanisms responsible for clopidogrel response variability are incompletely defined. Pharmacokinetic and pharmacodynamic differences in clopidogrel metabolism have been proposed to explain variable platelet inhibition. 

Assessing the Propagation of Genetic Variability in Drug Metabolism to Pharmacokinetics and Pharmacodynamics... 

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