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systemic "side" effects?

aNot discussed in simulations.

aNot discussed in simulations.

This PK/PD model essentially represents a mathematical translation of the scheme shown in Fig. 1 and is based on pharmacokinetic models for evaluating the pulmonary fate of inhaled drugs, developed independently by Byron and by Gonda [1-3]. In order to evaluate pulmonary selectivity, descriptors of the fate of the drug in the systemic circulation were incorporated. In addition, drug concentrations in the lung and in the systemic circulation were converted into the pharmacodynamic endpoints (degree of desired pulmonary effects and undesired systemic side effects) by linking free drug concentrations at the site of action (pulmonary or systemic organs) and the pharmacological response by a simple Emax model. This allows quantifying the degree of pulmonary targeting as the difference between local pulmonary effects and systemic side effects. In the case of glucocorticoids and a number of other inhalation drugs, a direct correlation between receptor occupancy and the degree of the pharmacological effects has been demonstrated; thus, receptor occupancy was used in the model as a surrogate marker of pulmonary effects and systemic side effects [4]. Differences in the receptor occupancy-time profiles for pulmonary effects and systemic side effects were then used to quantify pulmonary targeting. A typical result of such simulations is shown in Fig. 2. In accordance with previously published work [4-7], this model will be applied in the following paragraphs to visualize how pharmacokinetic and pharmacodynamic factors (Table 1) affect pulmonary targeting. Therefore, two or more hypothetical drug situations will be compared by simulations in subsequent sections of this chapter. Generally, these simulations will differ in only one property (e.g., clearance) while the rest of the PK and PD parameters remain the same.

Pharmacodynamic Factors Important for Pulmonary Targeting

The effects and side effects of a majority of inhalation drugs are mediated through membrane or cytosolic receptors. For glucocorticoids, the activity at the site of action is related to the receptor-binding affinity of the drug [8-10]. In the case of beta-2-adrenergic drugs, very good correlations were observed between in vitro indicators of drug activity in cell culture and the pharmacological activity in vivo [11,12]. Therefore, receptor-binding affinities or other in vitro parameters are often used in discussions describing the pharmacological properties of inhalation drugs at the site of action (e.g., in the lung). To evaluate the importance of the receptor potency of a drug on pulmonary targeting, two cases need to be differentiated. In the first case, such as for glucocorticoids, pulmonary effects and systemic "side" effects are mediated through the identical receptors in pulmonary and systemic tissues. In the second case, such as for beta-adrenergic drugs, two receptor sub-types (bi/b2 adrenergic receptors) are involved in the pulmonary and systemic side effects.

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