Model Based Dosage Optimization

Upon the selection of the appropriate PK/PD model, optimal dosage needs to be derived for each patient. Two new "models" are introduced at this point—the cost and the utility functions. The cost-utility analysis in PK/PD

modeling is relatively new and only the general theoretical principles will be discussed here. The cost of a therapy can be defined as the "expense" of the therapy due to an adverse effect, given the desired effect. Consider two drugs—one for relieving migraine headache and another for treating subarachanoid hemorrhage. Assume that both these drugs produce nausea. Given the indication (migraine versus stroke), the cost of the two therapies could be drastically different and hence may need different weighting. The physician(s) and/or the patient decide the "cost" of a therapy, which makes it highly subjective. The utility of a therapy can be defined as the advantage the therapy is providing over not taking the therapy, given the cost of declining therapy and the cost of drug-related toxicity.

Utility=f(Cost (No Therapy), Benefit, Cost (Toxicity) (3)

The utility function could have many components depending on the number of desired and undesired effects. Figure 2 shows the concentration (or dose)effect curves and the utility curve for various costs. Using the curves such as those in Fig. 2, a target exposure and the region of therapeutic equivalence should be determined. For example, the curve in Panel B for the stroke drug suggests an optimal target exposure of about 100. Further, the utility equivalence region would be, say, between 80 and 500% (asymmetric

FIGURE 2 The exposure (concentration or dose)-response (desired and undesired) relationships of a hypothetical drug (Panel A). The utility of the therapy was determined by subtracting the (cost adjusted) undesired effect from the desired effect. The utilities of the therapy for two different desired effects [disease reversal (stroke), migraine pain relief] given the same undesired effect (nausea) are shown in Panel B. Note that declining therapy for stroke has a high cost. The exposure that results in the maximum utility would be the optimal target exposure. In Panel B, the optimal target exposure would be about 100 for the stroke drug and zero for the antimigraine drug.

FIGURE 2 The exposure (concentration or dose)-response (desired and undesired) relationships of a hypothetical drug (Panel A). The utility of the therapy was determined by subtracting the (cost adjusted) undesired effect from the desired effect. The utilities of the therapy for two different desired effects [disease reversal (stroke), migraine pain relief] given the same undesired effect (nausea) are shown in Panel B. Note that declining therapy for stroke has a high cost. The exposure that results in the maximum utility would be the optimal target exposure. In Panel B, the optimal target exposure would be about 100 for the stroke drug and zero for the antimigraine drug.

intervals). The corresponding exposures can then serve as surrogates for individualizing drug exposures and establishing equivalence of two products.

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