Model direct versus indirect

More complex integrated PK/PD models are necessary to link and account for a possible temporal dissociation between the plasma concentration and the observed effect. Four basic attributes may be used to characterize PK/PD models First, the link between measured concentration and the pharmacological response mechanism that mediates the observed effect (direct versus indirect link) second, the response mechanism that mediates the observed effect (direct versus indirect response) third, the information used to establish the link between measured concentration and observed effect (hard versus soft link) and, fourth, the time dependency of the involved PD parameters (time variant versus time invariant) (Danhof et al., 1993 Steimer et al., 1993 Aarons, 1999 Lees et al., 2004). The expanded and early use of PK/PD modeling in drug discovery and development is highly beneficial for increasing the success rate of drug discovery and development and will most likely improve the current state of applied therapeutics. 

The difference between decision making on the basis of a standard alone and on the basis of a standard plus other information can be described as one aspect of the direct versus the indirect model. In the direct model, action is defined exactly as that needed to secure compliance with the standard, for example, as permit conditions for discharges to water that are calculated to meet an environmental standard in a river. The classic cases here are substances like ammonia or cadmium in rivers and other mandatory standards in various European directives. 

Some of the remaining studies did not necessarily observe incomplete catalyst wetting, but included this concept either directly as an adjustable parameter in the model to fit the observed conversion versus liquid mass velocity data,(7,9,13, 16-18), or indirectly via use of a correlation for liquid-solid contacting established for non-porous absorber column packings (11,19-20). 

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