Published ahead of print on July 31, 2003, doi:10.1164/rccm.200302-200OC
© 2003 American Thoracic Society
Lung Deposition and Systemic Availability of Fluticasone Diskus and Budesonide Turbuhaler in ChildrenUniversity of Southern Denmark; and Department of Paediatrics, Kolding Hospital, Kolding, Denmark Correspondence and requests for reprints should be addressed to Lone Agertoft, Department of Paediatrics, Kolding Hospital, DK-6000 Kolding, Denmark. E-mail: lone_agertoft{at}dadlnet.dk
Pharmacokinetic studies can be used to measure lung dose of inhaled drugs. The aim of this study was to compare the lung deposition of budesonide (BUD) inhaled from Turbuhaler (AstraZeneca, Lund, Sweden) and fluticasone propionate (FP) inhaled from Diskus (GlaxoSmithKline, London, UK) and to assess if the study design used for pharmacokinetic studies can be simplified. Plasma levels of BUD and FP were measured for 21 hours on five separate days in 15 patients aged 8 to 14 years: (1) Intravenous infusion of 200 µg BUD, (2) intravenous infusion of 200 µg fluticasone dipropionate, (3) inhalation of 800 µg BUD via Turbuhaler, (4) inhalation of 750 µg FP via Diskus, and (5) inhalation of BUD and FP on the same day. Charcoal was ingested to eliminate drug uptake from the gastrointestinal tract. The mean lung deposition of drug after Turbuhaler and Diskus inhalation was 30.8 and 8.0% when BUD and fluticasone were administered on separate days and 29.5% (BUD) and 7.6% (fluticasone) when the two drugs were inhaled on the same day. Lung deposition is four times higher in children after inhalation from Turbuhaler than after inhalation from Diskus. Pharmacokinetic studies with BUD and FP can be simplified because the two treatments can be administered on the same day.
Key Words: lung deposition • pharmacokinetics • inhaled corticosteroids • study design • children The phaseout of the chlorofluorocarbon propellants has led to the reformulation of pressurized metered dose inhalers (pMDI) with environmentally safer propellants such as hydrofluoroalkane-134a and the development of multidose dry powder inhalers (DPI). The in vitro output characteristics of these new inhalers vary markedly from each other and from those of chlorofluorocarbon inhalers. Thus, one inhaler may deliver up to four times as many fine particles (aerodynamic diameter < 5 µm) as another. Furthermore, marked differences are seen between the various inhalers in consistency of drug delivery, with the in vitro variation in drug delivery normally being markedly lower for pMDIs than from DPIs. The clinical relevance of these differences is not known. One study found that the DPI Turbuhaler showed less variability in lung deposition of both terbutaline and budesonide (BUD) than the pMDI despite the fact that in vitro the variability in drug delivery was markedly less for the pMDI (1, 2). Turbuhaler (AstraZeneca, Lund, Sweden) and Diskus (GlaxoSmithKline, London, UK) are two widely used DPIs. The in vitro characteristics of these two inhalers vary substantially: The in vitro variation in drug delivery is markedly less for Diskus than for Turbuhaler, whereas the number of particles with an aerodynamic diameter less than 5 µm is almost fourfold higher from Turbuhaler (3). However, this difference varies with inspiratory flow; the fine particle output being more reduced at low flow rates for Turbuhaler (4) than for Diskus (3). The clinical importance of these differences for lung deposition and clinical effect remains unknown. Lung deposition of inhaled drugs can be assessed in radiolabeled drug deposition studies and pharmacokinetic studies (5, 6). Both have their problems and limitations. Pharmacokinetic studies assess lung deposition by measuring systemic availability of the inhaled drug after blocking the gastrointestinal absorption of drugs deposited in the oropharynx and subsequently swallowed. When gastrointestinal absorption of the drug is blocked, the systemic availability of an inhaled drug is directly proportional to the amount of drug delivered to the airways. So, total lung deposition can be assessed by both methods. Regional deposition, however, cannot be assessed by the pharmacokinetic method. On the other hand, imaging techniques also determine the drug that does not reach the receptor if the drug is cleared by mucociliary clearance before absorption. Radiolabeled deposition studies expose the child to radiation, and pharmacokinetic studies use a complicated study design requiring several days stay at the hospital. The aim of the present study was to assess the lung deposition, absolute systemic availability, and basic pharmacokinetic parameters of BUD and fluticasone propionate (FP) inhaled from their respective DPIs (Turbuhaler and Diskus) in children with asthma. The secondary objective was to assess whether the design of pharmacokinetic studies with glucocorticosteroids can be simplified by administering more than one drug on each study day. Some of the results of this study have been previously reported in the form of abstracts (7, 8).
Six girls and nine boys aged 8 to 14 years (mean = 12 years) were studied. Their weight ranged from 25 to 54 kg (mean 42 kg), and their height ranged from 132 to 170 cm (mean 153 cm). The study was approved by the local Ethics Committee, and it was performed in accordance with the Declaration of Helsinki. Written and verbal informed consent was obtained from all children and their parents. FEV1 was higher than 80% of the predicted normal value on all study days. Patients received one of the following treatments in a random, crossover fashion: 800 µg of BUD (four inhalations of 200 µg) via Turbuhaler. 750 µg of FP (three inhalations of 250 µg) via Diskus. Intravenous infusion of 200 µg BUD. Intravenous infusion of 200 µg FP. On study day E, all patients inhaled both 800 µg BUD (4 inhalations of 200 µg) via Turbuhaler and 750 µg FP (3 inhalations of 250 µg) via Diskus in random order. All drug administrations took place in the afternoon. There was a minimum period of 6 days between each study day. Asthma drugs were discontinued 2 days before each visit. To prevent gastrointestinal absorption of the drug deposited in the oropharynx, a total of 45 g of charcoal mixed with water was received on all inhalation days as described earlier (9). In addition, mouthwash and gargling with water was undertaken immediately after each inhalation.
Inhalation Technique
Intravenous Infusion The following parameters were calculated from the plasma concentration curves, using routine nonparametric equations: AUC = area under the plasma concentration versus time curve extrapolated up to infinite time. Cmax = maximal concentration after inhalation. Tmax = time when Cmax occurred. Fabs = absolute bioavailability = lung deposition. MAT = mean absorption time.
Statistical Analysis
All the 15 patients completed the study. No adverse effects were seen from the various treatments. All plasma samples after drug administration had concentrations above the limit of quantification up to 16 hours and the vast majority also at 21 hours after administration. There was no statistically significant difference between the three inhalation study days in mean FEV1: 2.60 L (BUD), 2.59 L (FP) and 2.52 L (BUD and FP combined); mean peak inspiratory flow rate: BUD = 65.1 (range 59–70) L/minute, FP = 65.3 (range 59–72) L/minute, and BUD = 61.2 (range 55–69) L/minute and FP = 61.8 (range 57–75) L/minute (BUD and FP combined); or mean inhaled volume: BUD = 1.9 L, FP = 2.1 L, and BUD = 2.1 L and FP = 2.0 L (BUD and FP combined). The various pharmacokinetic parameters after intravenous administration and the ratios between FP and BUD are given in the online supplement. The half-life and mean residence time were approximately twice as long for FP and the volume of distribution twice as high as for BUD. AUC and clearance were similar for the two drugs. The mean plasma concentrations of the two drugs after the three days of inhalation (one BUD, one FP and one BUD + FP) are shown in Figure 1 and some estimated pharmacokinetic parameters from the 2 days when the two drugs were administered alone in Table 1 . Peak plasma concentrations were markedly higher and occurred earlier after BUD administration due to a much faster absorption of drug into the blood (mean difference in mean absorption time = 5.5 hours (95% confidence interval: 5.1; 6.0). Furthermore, the fraction of drug that became systemically absorbed from the lungs (= lung deposition) was 3.9 (95% confidence interval: 3.0; 4.9) times higher after Turbuhaler administration than after inhalation from Diskus. The coefficient of variation of lung deposition was approximately twice as high after Diskus as after Turbuhaler administration (p < 0.01).
The estimated pharmacokinetic parameters were virtually identical when each drug was administered separately and when they were administered together on the same day (Table 2 and Figure 1).
Our study is the first direct in vivo comparison of the lung deposition and pharmacokinetic parameters of the two most widely used DPIs in children with asthma and also the first to carefully validate simultaneous dosing techniques with different inhaled steroids. Turbuhaler was found to deliver almost four times as much drug to the lungs as Diskus. The finding of lung depositions around 30% of the nominal dose after Turbuhaler treatment is in good agreement with the results of other pharmacokinetic and radiolabeled drug studies in children of the same ages as in the present study (10, 11) but somewhat lower than the deposition reported in adults (12). This corroborates the findings of other studies reporting somewhat lower lung deposition in children than in adults (13, 14). To the best of our knowledge, lung deposition and pharmacokinetics of fluticasone from Diskus have not been studied previously in children. Lung deposition from Diskus was somewhat lower than that reported in adults (12, 15, 16). Otherwise, the findings in our study were in agreement with the findings in adults, i.e., a slower absorption, a higher volume of distribution, and a longer half-life of fluticasone than of BUD, whereas the clearance was similar for the two drugs (12). The fourfold higher lung deposition after Turbuhaler treatment was quite similar to the threefold ratio in lung deposition between the two devices reported in adults (12). Interestingly, a three- to fourfold difference in lung deposition mirrors the difference between the two inhalers in fine particle delivery (3, 17). This supports the notion that fine particle dose may be a good predictor of lung deposition as suggested in other studies with DPIs or hydrofluoroalkane-134a–beclomethasone (18, 19), although some studies with chlorofluorocarbon inhalers have not found any correlation (20). The 250 µg FP Diskus, which we used in the present study, has been found to deliver almost twice as high a fraction of the dose as fine particles as compared with the 50 µg inhaler (21). Therefore, it can be assumed that at least the same ratio between the two inhalers would apply also for lower strength inhalers of FP Diskus. The contribution of the orally deposited drug to the systemic availability of the drug differs between BUD and fluticasone, BUD having a lower first pass metabolism than fluticasone (22). Therefore, we used charcoal to block the gastrointestinal absorption of the two drugs. The charcoal block method has been described and validated previously in adults (23, 24). In children, charcoal has been shown to reduce the systemic availability of BUD after inhalation from Turbuhaler by 20% (9), which is what gastrointestinal absorption would be expected to contribute to the systemic availability of BUD. Gastrointestinal absorption normally results in a flat peak in the plasma concentration profile about 4 hours after inhalation (25). This was not seen in the present study, indicating that the charcoal did prevent gastrointestinal absorption and that this could not explain the marked difference in bioavailability between the two drugs. In vitro drug delivery from Diskus is more consistent than from Turbuhaler (3). Therefore, it was surprising that the variability in lung deposition was lower for Turbuhaler than for Diskus. The reason for this remains unknown. It may be due to the marked difference in particle size output between the two inhalers. Turbuhaler delivers three to four times as many fine particles as Diskus (3, 17). Fine particles may be deposited more consistently and/or more peripherally in the intrapulmonary airways than larger particles. Larger particles contain more drug, but may be deposited more centrally in the airways. Absorption of fluticasone from the airways was quite slow, and it could be speculated that some centrally deposited FP particles may have been ciliated upwards, swallowed, and escaped absorption. Because mucociliary clearance varies from time to time and from patient to patient, this might increase the variability in absorbed drug and reduce the estimate of lung deposition of FP. No other studies have compared the in vivo consistency of lung deposition of the two inhalers in children. However, other studies with terbutaline and BUD also found that in vitro variability does not necessarily predict in vivo variability (1, 2). Thus, in vivo Turbuhaler showed less variability in lung deposition of BUD than the pMDI despite the fact that in vitro the variability in drug delivery was markedly less for the pMDI. The implication of this is that clinicians should not put too much emphasis on in vitro comparisons of variability of drug delivery of different inhalers because they may be poor predictors of what happens in vivo. The results and conclusions in our study were exactly similar whether the two drugs were administered on separate study days or together on the same day. The between-day variations were very small. This information is important for the design of future pharmacokinetic studies. It seems that the various treatments do not have to be administered on separate days as being currently done. Two study days seem to be sufficient, one with intravenous administration and one with inhalation. This design would also have the advantage that the study conditions would be exactly similar for the various treatments. Before this approach is generally adopted, its feasibility for other drugs should also be validated. It is the drug in the airways that exerts the therapeutic effect. The drug deposited elsewhere has no therapeutic effect, but may have unwanted effects (candidiasis and, if absorbed, adverse systemic effects). Therefore, it is preferable to use an inhaler that consistently deposits a high proportion of the drug in the airways and little drug elsewhere. In the present study, this was achieved to a greater extent with Turbuhaler than with Diskus. What are the clinical implications of this? Increased lung deposition is normally associated with an increase in clinical effect until a plateau of the dose–response curve is reached (26–30). On the other hand, the drug has to be absorbed from the airway lumen and into the target cells to produce a clinical effect. From the target cells, the drug is goes into the systemic circulation. Therefore, a higher lung deposition of a given drug is normally also associated with greater systemic effects, which often parallel the increase in clinical effect. So, a higher lung deposition normally allows the use of lower doses but often does not change the relationship between clinical and systemic effects (the therapeutic ratio) to any great extent for a given drug. Although lung deposition influences the clinical and systemic effects, the results of the present study cannot be used to make conclusions about comparisons of the clinical or systemic effects of the two drug-inhaler devices. Other factors, including drug potency, receptor affinity, and pharmacokinetics also influence these outcomes. Thus a study in adults found that despite a threefold higher lung deposition of BUD Turbuhaler than fluticasone Diskus plasma cortisol suppression was similar for the two devices (12), although the dose–response curve for cortisol suppression may be steeper for fluticasone than for BUD (31). In 216 children, a dose reduction study found similar clinical and systemic effects of BUD Turbuhaler and fluticasone Diskhaler (32, 33). However, the marked difference in lung deposition between the two inhalers in the present study emphasizes the importance of also considering inhaler characteristics when comparing two drugs. This may be as important as other factors such as potency, receptor affinity, and pharmacokinetics.
Conclusions
L.A. has received $5,000 in 2002 and $7,000 in 2001 for speaking at scientific meetings or courses organized and financed by AstraZeneca and $10,000 in 2002 for speaking at scientific meetings or courses organized and financed by GlaxoSmithKline and L.A.'s institution has received an unrestricted educational grant from AstraZeneca and GlaxoSmithKline; S.P. has received $17,000 in 2002 and $15,000 in 2001 for speaking at scientific meetings or courses organized and financed by AstraZeneca and $10,000 in 2002 and $12,000 for speaking at scientific meetings or courses organized and financed by GlaxoSmithKline and L.A.'s institution has received an unrestricted educational grant from AstraZeneca and GlaxoSmithKline.
Supported by the Research Fund for Hospitals in Vejle County. The drug powder for intravenous injection was kindly provided by AstraZeneca, Sweden. This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Received in original form February 11, 2003; accepted in final form July 29, 2003
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