Lung distribution of inhaled drugs

I read with interest the comments made by Professor Henry Chrystyn in his recent editorial [1], concerning my review paper published in the same issue [2].

Unfortunately, Professor Chrystyn seems to have misunderstood the purpose of the review paper, which was to argue the case for lung deposition data in general as surrogate measures of efficacy in appropriate circumstances, to aid companies developing new inhaled drug products. The review made it clear that both radionuclide imaging techniques and pharmacokinetic evaluations may be used in the generation of lung deposition data, and was not intended as a comparison of methodologies.

While the review paper advocates the use of both imaging methods and pharmacokinetic methods, it is likely that the majority of studies will involve the former, for a very simple reason. Radionuclide imaging methods can be applied to any formulation which can be radiolabelled. The versatility of radionuclide imaging also explains why this methodology was used in the majority of case histories in the review paper [2]. Gamma scintigraphy will usually be the imaging method of choice [3], as outlined in a recent Concensus Statement from the British Association of Lung Research, BALR [4].

Conventional pharmacokinetic (PK) data are considered to have uncertain relevance for the efficacy of topically acting asthma drugs [5], which act on the airway surface and not from within the systemic circulation. Certain forms of specialized PK assessments enable either whole lung deposition, or an index of deposition, to be quantified. However, a particular PK method can only be applied to specific drugs or groups of drugs with appropriate PK profiles. The 30 min urinary excretion method has been used widely by Professor Chrystyn and his colleagues [6, 7] but most of their published studies have involved salbutamol, and there appears to be less experience with other drugs. The charcoal block PK method has been used extensively by the group based at AstraZeneca in Lund, Sweden [8, 9], but can only be applied to drugs whose gastrointestinal absorption can be blocked effectively by reasonable amounts of charcoal. Presumably this means that faced with a new drug whose deposition has not previously been assessed via PK data, it is necessary to set up and validate a whole new assessment method.

Professor Chrystyn suggests that gamma scintigraphy is not well validated. However, published studies have demonstrated (i) the accuracy of scintigraphic quantification of lung deposition [10], (ii) that gamma scintigraphy gives essentially the same data as a second independent method for quantifying whole lung deposition used simultaneously [11], and (iii) that indices of regional lung deposition have anatomical relevance [12]. In addition, radiolabelling validation data are routinely obtained as part of each scintigraphic investigation [13], and the recent review in this journal [2] relates lung deposition to the clinical response to asthma drugs. Most people would argue that this makes for a powerful validation package, especially compared with that available for some of the new PK methods, which need to be compared and validated against established methodology.

Concerns are raised about the use of radioactivity in imaging studies. It is customary to express the effective dose (ED) from radionuclide exposures [14], the sum of exposures to different organs via the use of weighting factors based upon radiosensitivity. In scintigraphic studies of inhaled drug delivery the amounts of radioactive material used are small, and the resulting EDs are low. The ED for a single study leg of a scintigraphic investigation of the lungs is usually less than 0.15 mSv. To put this into context, the ED from an abdominal X-ray is 0.70 mSv, while the typical annual radiation dose in the UK from radioactive background is 2.0 mSv. Any exposure to radioactive material (and indeed any exposure to drug in a pharmacokinetic study) involves risk, but this must be balanced against the benefits accruing from the results that are obtained.

Many gamma scintigraphy studies have used a multistage liquid impinger to carry out radiolabelling validation tests, but there is a strong trend, especially for pressurized metered dose inhalers, towards the use of an Andersen sampler, which divides the aerosol cloud into more fractions, and hence provides a more detailed examination of the size distributions of drug and radiolabel. This is recommended in recent BALR guidelines [4].

Professor Chrystyn is critical of studies commissioned for financial reasons, but I am unsure of the basis for his concern. The majority of companies developing novel products for pulmonary delivery regard lung deposition studies as milestone assessments along the road to obtaining regulatory approval. The scientific merit of these studies is demonstrated by their frequent acceptance for publication in peer-review journals.

The editorial argues that PK methods are likely to be more widely used in the future, and as the number of inhaled drug products, both for local and systemic delivery is steadily increasing, this view is probably correct. However, uncertainties remain over what some PK data actually tell us. For instance, it is suggested [1] that the amount of salbutamol excreted into the urine within the first 30 min after inhalation is the ‘effective lung dose’ and is a clinically more useful index than the total amount of drug deposited in the lungs. I know of no evidence to support these assertions. More research is needed to answer fundamental questions of this type, and Professor Chrystyn is quite right to draw attention to gaps in our knowledge.

Lung deposition data have a vital role to play in the assessment of inhaled drug delivery. By providing confirmatory in vivo data to support a programme of laboratory investigations, lung deposition data can provide a ‘bridge’ to a long and expensive clinical trials programme, which can then be entered with increased confidence of a successful outcome. No method is perfect, and both imaging and PK methods have roles to play. Lung deposition techniques provide such invaluable data that debating which method is, or is not, the ‘gold standard’ trivializes the issues and benefits nobody.