Pharmacodynamics dose-response curves

Pharmacodynamics is a discipline within the broader topic of pharmacology, which focuses on how a drug brings about a particular response, and the effective levels that are required in order to elicit such a response. Some of these basic data will have emerged from the research-based activities that initiate the development of most drugs today. However, considerable additional studies are required to establish detailed dose-response curves so that the optimum therapeutic level can be chosen. 

Purpose Explore Therapeutic Efficacy (dose ranging and dose-response curves, pharmacodynamics,... 

The sponsor of an NDA will normally have extensive pharmacokinetic and pharmacodynamic information available at the time the NDA is submitted. It may be appropriate to use data such as the slope of the dose-response curve in support of a contention that, for example, dissolution testing may be, in some instances at least, be sufficient for the demonstration of development bioequivalency. Certainly, we may conclude that the requirements for development bioequivalence should never be more rigorous than those applied in consideration of generic bioequivalency. 

Figure 3 Rodent pharmacodynamic effects versus CbjU for 6. Dashed lines represent a twofold separation from the in vitro functional assay EC50 (122 nM, dashed arrow). mSLA, mouse spontaneous locomotor activity mPPI, mouse prepulse inhibition DRC, dose-response curve SD, single dose. (See Color Plate 4.3 in the Color Plate Section.)...

Pharmacodynamic studies deal more specifically with how the drug brings about its characteristic effects. Emphasis in such studies is often placed upon how a drug interacts with a cell/organ type, the effects and side effects it induces, and observed dose-response curves. 

The range of doses and plasma concentrations that exhibited pharmacodynamic effects in animals, the nature of the effects, and the slope of the dose-response curve... 

In general, the between-gender variations did not result in obvious pharmacodynamic dose-response differences, but care must be exercised in drugs having a steep dose-response curve and/or... 

Inhalation of peptide leukotrienes has been shovm to induce a reproducible, robust, well-tolerated bronchoconstriction in humans. Because of this, most clinical studies of CysLTl antagonists have begun with an assessment of their in vivo potency through measurement of their ability to inhibit LT-induced bronchoconstriction. Because these studies can be done over a broad time range, they can also be used to determine human pharmacodynamic values. The most frequent measure was the shift in the LT-induced dose-response curve that is produced by a specified dose of a drug at a particular pretreatment time. Friedman (238) has reviewed the pulmonary-oriented clinical results obtained with most of the earlv peptide leukotriene antagonists and lipoxygenase inhibitors. 

To date there has been relatively little work correlating the pattern of deposition with the therapentic outcome or pharmacodynamic effects (118,124, 133-135). This perhaps is not too surprising, as most p-agonists are administered at or close to supramaximal doses and therefore generally administered close to the plateau of the dose response curve, while the therapeutic effects of inhaled steroids are observed over weeks and indeed for bronchial hypersre-sponsiveness further benefits are still being observed after a couple of years of therapy. 

The use of population pharmacokinetics and a sparse sampling approach allow each patients to contribute as few as two to four observations at predetermined times to an overall population. Use of the area under the curve (AUC) will minimise the number of samples required from each patient. Population models allow researchers to assess and quantify potential sources of variability in exposure and response in the target population. Population pharmacokinetics seeks to discover which measurable pathophysiological factors cause changes in the dose-concentration relationship and to what degree, so that the appropriate dosage can be recommended. The pharmacokinetic-pharmacodynamic approach has been used to assess sotalol syrup formulations (Shi et al, 2001). Ten blood samples were taken from... 

---