Introduction

The focus of this chapter is on the pharmacokinetic and pharmacodynamic aspects of inhalation drugs for topical delivery. For the last 30 years, pulmonary drug delivery has been successfully employed for topical therapy of pulmonary diseases, with the goal of achieving pronounced pulmonary effect while reducing systemic side effects. The degree of pulmonary targeting is determined by a number of pharmacokinetic (PK) and pharmacodynamic (PD) factors. This chapter will discuss these relationships and will review the pharmacokinetic and pharmacodynamic tools suitable for characterizing inhalation drugs.

FACTORS IMPORTANT FOR PULMONARY TARGETING Pulmonary Targeting—as Seen by a Pharmacokineticist's Eye

Figure 1 illustrates the sequence of events relevant to pulmonary drug administration. Once released from the device, a fraction of the delivered dose (respirable fraction) will be deposited in the lung, while larger particles will be

Figure 1 PK/PD model describing the fate of an inhaled drug. For a more detailed description, see Sec. 2.1.

deposited in the oropharynx. Drug deposited in the oropharynx will be swallowed and become subject to oral absorption. How much drug will be absorbed through the gastrointestinal (GI) tract will depend on how much drug is reaching the GI tract and the oral bioavailability of the drug. The fate of drug particles deposited in the lung is determined by two competing processes: (1) dissolution of the drug particles in the lung-lining fluid (if deposited as a particle) and subsequent uptake into pulmonary cells, followed by absorption, and (2) removal of solid drug particles from the upper part of the lung by mucociliary transport or in the alveolar region by macrophage uptake. Drug that has been removed from the lung is not available for inducing pulmonary effects; therefore pharmacologically relevant pulmonary drug levels (free drug levels are able to interact with the responsible receptors) will be determined by the complex equilibria between the mucociliary transport rate, dissolution rate of solid particles (if applicable), pulmonary tissue binding (only free drug levels are pharmacologically active), and absorption into the systemic circulation. One needs to realize that once the drug is dissolved in the lung the majority will be absorbed into the systemic circulation and that systemic spillover will occur, even for drugs exhibiting negligible oral bioavailability. The degree of systemic exposure (and the degree of systemic side effects) will depend on how much drug is reaching the systemic circulation through absorption from the lung and the GI tract and the efficiency of the drug removal system (metabolic or other clearance mechanisms). This scheme indicates that pulmonary selectivity or the degree of targeting is determined by an array of pharmacokinetic and pharmacodynamic factors, which are summarized in Table 1 and will be discussed here by using the PK/PD model for simulation purposes.

Table 1 Factors Affecting Pulmonary Targeting

Pulmonary components Systemic components

Table 1 Factors Affecting Pulmonary Targeting

Pulmonary components Systemic components

How much drug is deposited

• How much drug is swallowed?

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