It is logical to assume that the clinical efficacy of an inhaled drug is proportional to the amount of drug reaching the airways (see Pauwels et al, 1997; Selroos et al, 1996). This means that with a higher percentage lung deposition the same clinical efficacy can be achieved using a smaller nominal/label drug dose. Pulmicort^® and Bricanyl^® Turbuhaler^® deliver approximately twice as much drug to the lungs as the corresponding CFC pMDI (Tønnesen et al, 1994; Thorsson et al, 1994), Diskus™/Accuhaler™ or Diskhaler™ (Thorsson et al, 1997, 2001). Furthermore, if more drug reaches the lungs from a given dose this means that there is less deposition in oropharynx, thus fewer local side effects. For drugs such as Pulmicort^® and Bricanyl^®, for which there is a small amount of absorption from the GI tract, a better therapeutic ratio is achieved with Turbuhaler^® vs. devices with lower lung deposition and higher oropharyngeal deposition (Borgström, 1998).

References

Borgström L. Local versus total systemic bioavailability as a means to compare different inhaled formulations of the same substance. J Aerosol Med 1998;11(1):55-63.

Pauwels R, et al. Airway deposition and airway effects of anti-asthma drugs delivered from metered-dose inhalers. Eur Respir J 1997;10:2127-38.

Selroos O, et al. Delivery devices for inhaled asthma medication. Clinical implications of differences in effectiveness. Clin Immunother 1996;6:273-99.

Thorsson L, et al. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered dose inhaler. Eur Respir J 1994;7:1839-44.

Tønnesen F, et al. Bronchodilating effect of terbutaline powder in acute severe bronchial obstruction. Chest 1994;105:697-700.

Thorsson L, et al. Pharmacokinetics and systemic activity of fluticasone propionate and budesonide. Br J Clin Pharmacol 2001;52:1-15.

There are two main ways to measure lung deposition. In the first method, the drug formulation is labelled with a radioactive marker; the subject inhales the formulation and the fate of the inhaled drug is followed by an external scanning camera.

The other lung deposition method uses a traditional pharmacokinetic approach. At inhalation, a large portion of the inhaled drug will impact in the oropharynx and this portion will be swallowed and some of this will appear in the systemic circulation. Drug reaching the lungs will also appear in the systemic circulation. Thus, if the portion of the inhaled drug that reaches the systemic circulation via gastrointestinal absorption is blocked it is possible to use plasma data as a measurement of lung deposition.

Such a "pure lung situation" can be created by blocking the gastrointestinal uptake by oral intake of activated charcoal before and after inhalation of the drug. This method has been used for a number of drugs such as terbutaline, budesonide, formoterol and salbutamol.

There is a good agreement between the two methods if performed to high standards.

References

Borgström L, Nilsson M. A method for determination of the absolute pulmonary bioavailability of inhaled drugs: terbutaline. Pharm Res 1990;7:1068-70.

Pauwels R, et al. Airway deposition and airway effects of antiasthma drugs delivered from metered-dose inhalers. Eur Respir J 1997;10(9):2127-38.

Very high lung deposition is difficult to achieve as the interaction between the human anatomy and the aerosol particles will result in unavoidable losses on their way to the target in the lung. Thus, fine particle fraction (FPF), i.e. the proportion of a dose that is below a certain size (usually 5 µm), is one of the main predictors of lung deposition. Smaller particles will have a better chance of avoiding impaction in the oropharynx and a higher FPF will result in a higher lung deposition.

The FPF for currently marketed dry powder inhalers differs widely, ranging from 10-60% of the delivered dose. Diskus™/Accuhaler™ is an example of a dry powder inhaler that delivers a low FPF - the drug is combined with a lactose carrier that has a low capacity for producing fine particles. In addition, the dose from Diskus™/Accuhaler™ is released directly from the cavity in the blister into the inhaled air stream and travels without passing any additional deaggregation steps before reaching the patient. In Turbuhaler^®, spheronised particles coupled with efficient deaggregation of the drug in the spiral shaped channels of the mouthpiece results in a high FPF being generated at the patient's inhalation. For example, in one study Pulmicort^® Turbuhaler^® delivered a FPF of 44% in simulated inhalation profiles in 8-year-old children but fluticasone Diskus™/Accuhaler™ only delivered 20% (Bisgaard et al, 1998).

Efficient deaggregation relies on high air velocities. Patients, therefore, have to generate a slightly higher effort to achieve this better deaggregation, but the benefit is that a higher fraction of the given drug will reach the target area in the lungs. As discussed earlier, inspiratory effort is not greatly affected even in patients with acute asthma or COPD.

Reference

Bisgaard H, et al. Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma. Eur Respir J 1998;11:1111-5.

Most of the drug is absorbed into the airway tissue but some will be cleared from the lungs by mucociliary clearance before being absorbed. To be absorbed inhaled drugs have to be dissolved in the bronchial mucosal fluid. Inhaled steroids have been investigated in this respect and the dissolution time varies greatly between different substances (budesonide: 6 min; fluticasone propionate: >8 h; BDP: >5 h), as does their water solubility (budesonide: 16 µg/mL; fluticasone propionate: 0.14 µg/mL; BDP: 0.13 µg/mL).

A long dissolution time indicates that less drug is available for absorption. The availability at the effector site will be dependent on lung function and mucociliary clearance. For rapidly dissolving corticosteroids, e.g. budesonide, the disease severity does not affect effector site availability and results obtained in studies with healthy subjects are relevant for patients with various degrees of airway obstruction. Slowly dissolving corticosteroids, e.g. fluticasone propionate, with a long dissolution time, are more affected by mucociliary clearance and hence a difference in availability is seen between patients with severe airway obstruction and those with mild disease or healthy subjects (Edsbäcker, 2002).

Several investigators have studied this difference and have shown that around half the dose of fluticasone propionate is lost for patients with moderate to severe asthma or COPD (Figure).

Ratio of amount of drug available in asthma patients:control subjects for budesonide (BUD) and fluticasone propionate (FP). Data from (1) Brutsche et al (2000), (2) Harrison and Tattersfield (2003), (3) Singh et al (2003).

References

Brutsche MH, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: A randomised crossover study. Lancet 2000;356:556-61.

Edsbäcker S. Uptake, retention, and biotransformation of corticosteroids in the lung and airways. In: Schleimer RP, O´Byrne PM, Szefler SJ, Brattsand R (eds.). Inhaled steroids in asthma. Optimising effects in the airways. Marcel Dekker, New York 2002; 213-44.

Harrison TW, Tattersfield AE. Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects. Thorax 2003;58:258-60.

Singh SD, et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease. Br J Clin Pharmacol 2003;55:375-81.

Variability in lung deposition should not be confused with variability in in vitro parameters. Turbuhaler^® delivers microgram amounts of powder and, therefore, it is not surprising that in vitro laboratory tests with Turbuhaler^® show a larger dose variability than, for example capsule- or blister-based powder inhalers, which use much larger amounts of carrier lactose powder. It is important to note that there is no correlation/predictability between the in vitro dose variability, as measured in laboratory tests and the in vivo variability, measured as lung deposition.

In a study examining variability between Turbuhaler^® and other DPIs in 15 children aged 8 to 15 years, mean lung deposition was 30.8% for Pulmicort^® Turbuhaler^® (coefficient of variation, CV 24.2%) and 8.0% for fluticasone Diskus™/Accuhaler™ (CV 61.2%) (Agertoft and Pedersen, 2003). Thus, Turbuhaler^® clearly has a lower in vivo dose variability than the dry powder inhaler Diskus™/Accuhaler™.

In a study in adult healthy subjects and patients with mild asthma the in vivo dose variability was significantly lower for Pulmicort^® Turbuhaler^® compared with fluticasone Diskus™ (Thorsson et al, 2001, 2003). The variability expressed as CV was 21% for Turbuhaler^® and 40% for Diskus™/Accuhaler™ in healthy volunteers (p<0.05), and 9% and 37%, respectively, in patients with mild asthma (p<0.01).

References

Agertoft L, Pedersen S. Lung deposition and systemic availability of drug from two different dry powder inhalers in children with asthma. Am J Respir Crit Care Med 2003;168:779-782.

Thorsson L, et al. Pharmacokinetics and systemic activity of fluticasone via Diskus^® and pMDI, and of budesonide via Turbuhaler^®. Br J Clin Pharmacol 2001;52:529-38.

Thorsson L, Edsbäcker S. Less variability in lung deposition of budesonide via Turbuhaler^® than of fluticasone via Diskus^®/Accuhaler^® and pMDI in adults. Am J Respir Crit Care Med 2003;167(7 Suppl):A896.

While there are a number of causes for variability, there is an overall link between low lung deposition and high variability, and high lung deposition and low variability (Borgström et al, 2005). In fact a high mouth deposition seemed to be the primary source of a high variability. There are several underlying reasons for the high lung deposition with Turbuhaler^®, but the main one is the properties of the pharmaceutical formulation that results in a high fine particle fraction (FPF) at inhalation. In addition, to be absorbed and hence effective, inhaled corticosteroids have to dissolve in the bronchial mucosal fluid. Thus, rapidly dissolving inhaled corticosteroids, such as budesonide, will not be affected by mucociliary clearance; however, slowly dissolving inhaled corticosteroids, such as fluticasone, could be more affected by mucociliary clearance, which adds to a higher in vivo variability. (Read more about the influence of mucociliary clearance on the effects of inhaled steroids)

Lung deposition variability for different amounts deposited in the lungs following inhalation via different types of inhaler. Data from Borgström et al (2005). SMI = Soft Mist Inhaler.

Reference

Borgström L, et al. Throat deposition can explain the variability in lung deposition. J Aerosol Med 2006;18(1):97