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Figure 2 Effect of receptor affinity on pulmonary (upper line) and systemic (lower line) receptor occupancies. The simulations try to illustrate pulmonary selectivity of an inhaled drug by utilizing PK/PD relationships and selecting receptor occupancy as a surrogate marker to predict the pulmonary and systemic effects. The difference (shaded area) between the area under the curve (AUC) for pulmonary and systemic receptor occupancy-time profiles indicates the degree of pulmonary targeting. Simulations A and B depict two hypothetical drugs with different receptor-binding affinities; however, by adjusting their dose, the differences in their receptor-binding affinities can be compensated. Both the drugs display the pulmonary and systemic side effects by interacting with the same subtype of receptors. From the figure it is clear that by adjusting the dose of the drug displaying lower receptor-binding affinity, identical pulmonary selectivity can be achieved. The EC50 value and the dose were modulated to obtain identical pulmonary selectivities, whereas other parameters (such as clearance, volume of distribution) were fixed during the simulation.

ECeu (Lung, Sys) " 0.1 nrj'nil. 750 ,ig do» LCyj (Lung. Sys) = 0-033 nglmL, £50 pg do»

If the "same" receptors are mediating pulmonary and systemic effects, simulations (Fig. 2) show that pulmonary targeting (the difference between lung and systemic receptor occupancy) is not affected by different receptor-binding affinities, as long as these differences are being considered by adjusting the dose (double the dose for a drug with half of the receptor affinity). This means that a low receptor-binding affinity can be compensated by an increase in the dose. Thus, the importance of a high receptor-binding affinity for promoting pulmonary selectivity, often used by marketing publications, should be questioned.

In the second case (Fig. 3), where pulmonary and systemic effects are mediated through different receptors (e.g., beta-2-adrenergic drugs), a high binding selectivity (high affinity to the b2 receptors, low affinity to the bi receptor) is important for the pulmonary selectivity, and drug candidates with the highest degree of selectivity should be selected.

Figure 3 Simulations (A, B, and C) showing pulmonary (upper line) and systemic (lower line) receptor occupancies for a hypothetical beta-2-adrenergic drug that display the desired (pulmonary) and undesired (systemic) effect by occupying two different types of receptors. Cases A, B, and C show the occupancy profiles for pulmonary and systemic effects when the receptor affinity of the drug in the lung (for beta-2 receptors) remains unchanged but decreases (for beta-1 receptors) at the systemic organs (compare with A). Thus pulmonary selectivity is achieved at the pharmacodynamic level. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D.

Figure 3 Simulations (A, B, and C) showing pulmonary (upper line) and systemic (lower line) receptor occupancies for a hypothetical beta-2-adrenergic drug that display the desired (pulmonary) and undesired (systemic) effect by occupying two different types of receptors. Cases A, B, and C show the occupancy profiles for pulmonary and systemic effects when the receptor affinity of the drug in the lung (for beta-2 receptors) remains unchanged but decreases (for beta-1 receptors) at the systemic organs (compare with A). Thus pulmonary selectivity is achieved at the pharmacodynamic level. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D.

Pharmacokinetic and Biopharmaceutical Factors Important for Pulmonary Targeting

Oral Bioavailability

A significant portion of drug delivered by metered-dose inhaler (MDI) or dry powder inhalation (50-90%) reaches the GI tract. The overall amount depends on how much drug is deposited in the oropharynx and swallowed and how much pulmonary deposited drug is removed from the lung by mucociliary clearance, ultimately reaching the GI tract. The oral bioavailability of the drug (F), determined quite often by the hepatic or prehepatic first-pass effect, serves as the final gatekeeper in determining how much drug enters the systemic circulation. Figure 4 shows that the drug with the lower oral bioavailability is more effective in promoting pulmonary targeting. Fluticasone propionate (FP) has been reported to have the lowest bioavailability (< 1%) [13,14]. Bioavailabilities of currently used inhaled glucocorticoids range from 0% to 40% [15-19]. Similarly, oral bioavailabilities of short-acting beta-2-adrenergic drugs vary significantly, from 1.5% to about 50% [11]. These differences are likely to have an impact on the degree of pulmonary selectivity. According to Rohatagi et al., oral bioavaila-bilities of 25% or less should not induce clinically relevant systemic side effects

% Oral Bioavailability (F)

Figure 4 Effect of oral bioavailability (F-value) on pulmonary (upper line) and systemic (lower line) receptor occupancies. The F-value mainly determines the input of the swallowed drug (G.I.) into the systemic circulation. Simulations (A-C) are shown for 100, 30, and 1% oral bioavailability, whereas the other parameters, such as clearance, volume of distribution, and dose, remain unchanged. With a decrease in the oral bioavailability, there was a significant increase in the degree of pulmonary targeting (see D).

% Oral Bioavailability (F)

Figure 4 Effect of oral bioavailability (F-value) on pulmonary (upper line) and systemic (lower line) receptor occupancies. The F-value mainly determines the input of the swallowed drug (G.I.) into the systemic circulation. Simulations (A-C) are shown for 100, 30, and 1% oral bioavailability, whereas the other parameters, such as clearance, volume of distribution, and dose, remain unchanged. With a decrease in the oral bioavailability, there was a significant increase in the degree of pulmonary targeting (see D).

as long as a large pulmonary deposition is responsible for a limited amount of drug being swallowed [20].

Systemic Clearance

Systemic clearance is the pharmacokinetic factor describing the efficiency of the body to eliminate systemically absorbed drug. The cumulative systemic exposure, as indicated by the area under the drug plasma concentration time profile, is determined by the amount of drug entering the systemic circulation and the systemic clearance. Thus, if an inhaled drug shows pronounced systemic clearance, systemic exposure will be reduced. This is reflected in simulations shown in Fig. 5 that indicate increased pulmonary targeting with increasing

Figure 5 Effect of systemic clearance (CL) on pulmonary (upper line) and systemic (lower line) receptor occupancies. Simulations A, B, and C are shown for an increasing CL values of 10, 90, and 300L/hr, respectively, whereas the other parameters, such as volume of distribution and dose, remain unchanged. An increase in CL (10-300 L/hr) produces a significant increase in the difference (AUC pulmonary-AUC systemic) between pulmonary and systemic receptor occupancies, thus indicating that CL is very beneficial in achieving pulmonary selectivity for an inhaled drug.

Clearance IL-'-n

Figure 5 Effect of systemic clearance (CL) on pulmonary (upper line) and systemic (lower line) receptor occupancies. Simulations A, B, and C are shown for an increasing CL values of 10, 90, and 300L/hr, respectively, whereas the other parameters, such as volume of distribution and dose, remain unchanged. An increase in CL (10-300 L/hr) produces a significant increase in the difference (AUC pulmonary-AUC systemic) between pulmonary and systemic receptor occupancies, thus indicating that CL is very beneficial in achieving pulmonary selectivity for an inhaled drug.

systemic clearance. Most inhaled glucocorticoids are predominantly cleared by hepatic metabolism so efficiently that their clearance values are close to the liver blood flow [16,21 -23]. For new drug developments in this field this means that further improvements (increases) in the systemic clearance can be achieved only by incorporating extrahepatic clearance mechanisms, for example, by identifying glucocorticoids that are metabolized in the blood [24]. The challenging aspect of such an endeavor is to find enzymatic systems that are present in the blood at sufficient concentrations but that are not expressed in the pulmonary cells, because rapid pulmonary inactivation would result in very low pulmonary drug levels and insufficient pulmonary effects. It is therefore essential that such drugs be stable enough in the lung tissue to show sufficient pulmonary presence.

Volume of Distribution/Plasma Binding

Quite often, the half-life of a drug is used as an indicator of systemic exposure. It is determined by clearance and volume of distribution. While clearance describes the ability of the body to eliminate the drug, volume of distribution (Vd) is the pharmacokinetic parameter that provides an estimate of the extent of distribution of the drug into the tissue compartments.

For lipophilic drugs, which are able to cross membranes and enter most of the tissue compartments (volume of the tissue compartment, Vt), the volume of distribution (Vd) can be calculated by knowing the volume of the plasma (Vp) and the fraction of drug unbound in the plasma (fu) and in the tissue (fuT):

f uT

The more pronounced the tissue binding is over plasma protein binding, the larger will be the value of Vd and thus the more drug will be in the peripheral compartment. While this induces a longer half-life of the drug, the degree of pulmonary selectivity is not significantly affected (Fig. 6). Therefore, drugs with a long half-life are not necessarily bad inhalation drugs, if the long half-life is due to a pronounced tissue binding.

Another aspect of tissue and plasma protein binding should be discussed. More lipophilic drugs are currently in development that show both increased tissue and plasma protein binding and, as a consequence, small fu and fuT values. Yet there are no dramatic increases in the estimates of volume of distribution, because bothfu and fuT are increased. With a decrease in the overall fraction of free drug, the effects (local and systemic) will be smaller than those of an equivalent drug with equivalent volume of distribution but lower tissue and plasma protein binding. In this case, the drug with the higher degree of binding but otherwise identical properties will show reduced systemic side effects and reduced pulmonary effects

Figure 6 Effect of volume of distribution (Vd) on pulmonary (upper line) and systemic (lower line) receptor occupancies. Simulations, A, B, and C are shown for increasing Vd values of 150, 400, and 1500 L, respectively, whereas the other parameters, such as clearance and dose, remain unchanged. An increase in Vd (100-1500L) produces only a slight increase in the difference (AUC pulmonary-AUC systemic) between pulmonary and systemic receptor occupancies, thus indicating that Vd does not seem to be that significant in modulating pulmonary selectivity. As a result, drugs with similar clearance but different half-lives due to differences in Vd will produce approximately equivalent degrees of pulmonary and systemic effects.

Figure 6 Effect of volume of distribution (Vd) on pulmonary (upper line) and systemic (lower line) receptor occupancies. Simulations, A, B, and C are shown for increasing Vd values of 150, 400, and 1500 L, respectively, whereas the other parameters, such as clearance and dose, remain unchanged. An increase in Vd (100-1500L) produces only a slight increase in the difference (AUC pulmonary-AUC systemic) between pulmonary and systemic receptor occupancies, thus indicating that Vd does not seem to be that significant in modulating pulmonary selectivity. As a result, drugs with similar clearance but different half-lives due to differences in Vd will produce approximately equivalent degrees of pulmonary and systemic effects.

at a given concentration. Systemic side effects are "hard" parameters in clinical studies, for concentration-response relationships can easily be detected, whereas pulmonary effects are generally "soft" parameters (concentration-effect relationships are difficult to detect). Such high-binding drugs given at identical doses might show very high safety profiles (low systemic effects) while antiasthmatic effects are not statistically significantly different, because of the soft pulmonary surrogate markers. In this case the drug with a high plasma/tissue binding will suggest a higher safety profile.

Pulmonary Deposition Efficiency

Drug deposition to the lungs varies significantly with the type of delivery device. It seems obvious that a pulmonary delivery device with higher pulmonary deposition will be more suitable for achieving pulmonary targeting. This is because the more efficient devices not only increase the amount of drug in the lung but also reduce the amount of drug that is available for absorption from the GI tract. In recent years, improvements in the design of delivery devices have increased pulmonary deposition from 10-20% to up to 40% [25,26]. Simulation studies confirm the obvious, that high pulmonary deposition is beneficial for the degree of pulmonary targeting. However, it is especially beneficial for a drug with high oral bioavailability, because an increase in pulmonary deposition will lead to a reduction in the fraction of the dose available for oral absorption [4]. A high pulmonary deposition is not important at all for a drug with negligible oral bioavailability, because under these conditions, drug entering the GI tract will not be able to induce systemic side effects. However, in this case, using a device with higher pulmonary deposition would permit dose adjustments by reducing the emitted dose.

Daily Dose

Inhaled drugs are often used within a rather broad dose range, with low doses used in patients with light asthma and higher doses prescribed in patients with severe asthma. It might therefore be of interest to evaluate whether pulmonary targeting depends on the prescribed dose. At very low doses of an inhaled drug, most of the pulmonary and systemic receptors are not occupied; thus relatively smaller pulmonary and systemic effects are observed (Fig. 7). As the dose increases, the differences between pulmonary and systemic effects become more pronounced. Finally, at the higher doses, almost all the receptors are occupied both systemically and in the lung, thus leading to loss of targeting. The simulation suggests that there exists an optimal dose that would provide maximal lung selectivity. If a patient needs higher doses to manage the asthma, targeting is lost, and physicians should consider switching the patient from inhalation to oral drug treatment, because the cost/benefit ratio is improved.

Frequency of Dosing

Currently, there is a tendency to maintain patients on once-daily doses of inhaled drugs. While the feasibility of the once-daily dosing depends on a number of drug-specific factors and the disease state itself, one might ask what general relationships exist between dosing frequency and selectivity. As shown in Fig. 8, pulmonary selectivity is improved if the same daily dose is administered in multiple smaller doses throughout the day, for this will extend the time for which

Figure 7 Effect of inhaled dose on pulmonary selectivity. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. Simulations are shown for increasing dose values of 30, 300, and 3000 mg. At very low doses, relatively smaller pulmonary and systemic effects are observed, because most of the systemic and pulmonary receptors are unoccupied. With a subsequent increase in the dose, both the pulmonary and systemic effects increase, and so does the difference between them (greater pulmonary selectivity). However, with a further decrease in the dose there is a loss in pulmonary targeting due to the saturation of both pulmonary and systemic receptors.

Figure 7 Effect of inhaled dose on pulmonary selectivity. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. Simulations are shown for increasing dose values of 30, 300, and 3000 mg. At very low doses, relatively smaller pulmonary and systemic effects are observed, because most of the systemic and pulmonary receptors are unoccupied. With a subsequent increase in the dose, both the pulmonary and systemic effects increase, and so does the difference between them (greater pulmonary selectivity). However, with a further decrease in the dose there is a loss in pulmonary targeting due to the saturation of both pulmonary and systemic receptors.

higher pulmonary levels are present (prolonging the pulmonary drug exposure time). Thus, increasing the frequency of dosing will have a beneficial effect, especially for drugs that are absorbed relatively fast from the lung. This was also demonstrated in a clinical study, which showed that repeated dosing was beneficial in enhancing antiasthmatic efficacy of budesonide [27]. However, increasing the frequency of dosing has its limitations because of problems with patient compliance; therefore other ways of prolonging the contact time of the drug within the lung should be evaluated.

Doses par day

Figure 8 Effect of dosing regimen at steady state on pulmonary selectivity. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. Additional doses are shown in D. A daily dose of 400 mg was administered as one single dose (A), 200 mg b.i.d (B), or 100 mg q.i.d. (C). Simulations show that a higher frequency of dosing results in greater pulmonary selectivity.

Doses par day

Figure 8 Effect of dosing regimen at steady state on pulmonary selectivity. Pulmonary selectivities [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. Additional doses are shown in D. A daily dose of 400 mg was administered as one single dose (A), 200 mg b.i.d (B), or 100 mg q.i.d. (C). Simulations show that a higher frequency of dosing results in greater pulmonary selectivity.

Pulmonary Residence Time

It seems obvious that the pulmonary fate of an inhaled drug particle is vital for its targeting. Generally, deposited drug particles will dissolve in the pulmonary lining fluid or will be released from delivery systems, such as microspheres and liposomes, and diffuse to the site of action, where they will induce the desired effect and subsequently be absorbed into the systemic circulation. In addition, solid drug particles or macromolecular compounds can be removed from the lung by the mucociliary transporter (predominantly in the upper respiratory tract) or by macrophage uptake and lymphatic removal.

Pulmonary absorption from the lung into the systemic circulation occurs for lipophilic drugs, generally by diffusion across lipophilic membranes [28-32], while hydrophilic drugs are absorbed through water-filled channels [30,33-35]. In addition, active or facilitated transport can be involved in drug absorption [31,36,37]. Because of the physiology of the lung (thin membranes, high number of pores) and the distinct sink conditions realized in the lung due to the high pulmonary blood flow, absorption of inhaled drugs across the pulmonary membranes is often relatively fast (unless it is a drug with very high molecular weight), and inhaled drug in solution will consequently leave the lung in a very short period of time. Thus, the pulmonary residence time of inhaled drugs given as a solution is generally very short. This also indicates that other factors (e.g., the dissolution rate of the inhaled drug particle or the release rate from the drug delivery system) might represent the rate-limiting steps for how long the drug resides in the lung.

Figure 9 shows the relationship between the dissolution rate of inhaled drug particles and pulmonary selectivity, with the assumption that once drug is dissolved, it will be absorbed relatively fast into the systemic circulation. If the drug particle dissolves quickly (or the drug was given as a solution), it will be absorbed rapidly into the systemic circulation and thus reside in the lung for only a short period of time (Fig. 9, short pulmonary residence time). As a result, lung selectivity (higher free drug levels in the lung than in the systemic organs) will last for only a very short period of time, and the free unbound drug in the lung and the systemic circulation will be identical shortly after inhalation, leading to loss in targeting. This does not imply a lack of pulmonary effect, but the beneficial effects could be accompanied by significant systemic side effects. If the pulmonary dissolution rate is slowed down, drug concentrations in the lung will be greater over an extended period of time, compared to the levels in the systemic circulation. Thus, a sustained pulmonary drug release is very beneficial for lung targeting (Fig. 9). However, when the drug is delivered to the upper part of the lung, mucociliary transport needs to be considered, because it will remove undissolved drug particles, resulting in loss of efficacy and pulmonary targeting. As a result, there is an optimal dissolution rate for which maximum targeting will be observed (Fig. 9). It further needs to be stated that the situation is somewhat different in the alveolar region of the lung, because mucociliary clearance is not that pronounced, and an optimum release rate might not easily be defined.

As mentioned earlier, the absorption rate of a number of drugs is often too fast to express maximum targeting. Thus, a significant body of work has concentrated on the design of drug delivery systems that slow down this process and provide the drug with an increased pulmonary residence time. There have been several different approaches to improve the pulmonary residence time of inhaled drugs [38]. These include the use of liposomes [39-41], microspheres [42-45], ultrathin coatings around drug dry powders [46], the use of new excipients such as oligolactic acid [47] and trehalose derivatives [38], or simply

Figure 9 Effect of pulmonary dissolution rate on pulmonary selectivity. The dose of 300 mg was allowed to dissolve immediately (A), with a half-life of 3 hr (B), or with a half-life of 24 hr (C). Pulmonary selectivity [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. The dose was given once a day at steady state. A slower release/dissolution of the drug in the lung does significantly increase pulmonary selectivity; however, very slow dissolution rates further decrease pulmonary selectivity as the undissolved drug particles are removed from the lung by the mucociliary transport system.

Figure 9 Effect of pulmonary dissolution rate on pulmonary selectivity. The dose of 300 mg was allowed to dissolve immediately (A), with a half-life of 3 hr (B), or with a half-life of 24 hr (C). Pulmonary selectivity [area between pulmonary (upper line) and systemic (lower line) receptor occupancies] observed in A-C are summarized in D. The dose was given once a day at steady state. A slower release/dissolution of the drug in the lung does significantly increase pulmonary selectivity; however, very slow dissolution rates further decrease pulmonary selectivity as the undissolved drug particles are removed from the lung by the mucociliary transport system.

the use of slow-dissolving lipophilic drugs. There are also biological approaches to prolong the time the drug stays in the lung. For example, long-acting beta-adrenergic drugs bind tightly to pulmonary cell membranes [48], and this fraction of drug provides a reservoir that feeds drug slowly to the receptor. Similarly, reversible formation of fatty acid esters has been described for glucocorticoids. Glucocorticoids will enter the cell, and a fraction of the drug is converted into highly lipophilic inactive ester derivatives that are unable to leave the cell. The trapped ester can also act as depot for the active corticosteroid in the lung because it can be slowly be reactivated into the active glucocorticoid [49-52]. Such systems may serve as alternative mechanisms for enhancing pulmonary residence, if a significant fraction of the drug deposited in the lung will be captured.

Prodrugs

A few inhalation drugs, such as beclomethasone dipropionate, are prodrugs, which are not able to interact with the receptor themselves but need to be metabolized (activated) into an active metabolite before they can induce their desired effects. This activation can happen in the lung or after absorption from the lung or the GI tract. Prodrugs that are absorbed into the systemic circulation without prior activation and that are activated in the systemic circulation can induce pulmonary effects only after redistribution into the lung. Thus free drug levels in the systemic circulation and in the lung will be similar and no targeting will be observed. Therefore in order to obtain optimal pulmonary selectivity, these drugs need to be activated predominantly in the lung. It is not trivial in clinical pharmacological studies to show the degree of pulmonary activation of such prodrugs, because such studies need to include the intravenous administration of drug and active metabolite.

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