Pulmicort in relation to other inhaled corticosteroids
Clinical efficacy of Pulmicort Turbuhaler - deposition figures" ]
In vitro vs. in vivo variability" ]
Pulmicort Turbuhaler vs. Pulmicort pMDI" ]
Pulmicort Turbuhaler vs. BDP pMDI" ]
Pulmicort Turbuhaler vs. fluticasone propionate Diskhaler and Diskus" ]
The importance of therapeutic index" ]
Clinical efficacy of Pulmicort Turbuhaler - deposition figures
The local anti-inflammatory activity of inhaled corticosteroids in the airways is dependent on the amount of drug deposited in the airways. Pulmicort delivered via a pressurized metered dose inhaler gives an airway deposition of around 15-20%. Pulmicort Turbuhaler delivers approximately twice as much drug to the airways, 25-40% (1). The higher lung deposition achieved with Turbuhaler may compensate for the higher receptor affinity seen with more lipophilic steroids such as fluticasone propionate delivered via Diskus™ or Diskhaler™ as these two inhaled steroids appear to be equally effective on a nominal µg basis in patients with asthma (2-4).
Lung dose and suppression of plasma cortisol after administration of fluticasone via Diskus and pMDI, and budesonide via Turbuhaler
Reference:
1. Thorsson L et al.: Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered dose inhaler. Eur Respir J 1994; 7: 1839-1844.
2. Kuna P et al. A randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial of the minimal effective dose of budesonide and fluticasone dry-powder inhalers in adults with mild to moderate asthma. Clin Ther 2003; 25: 2182-97.
3. Agertoft L, Pedersen S. A randomized double-blind dose reduction study to compare minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997; 99: 773-780.
4. Thorsson L et al. Pharmacokinetics and systemic activity of inhaled fluticasone propionate via Diskus and pMDI and budesonide via Turbuhaler. Br J Clin Pharmacol 2001; 52: 529-38.
In vitro vs. in vivo variability
Laboratory studies have shown greater dose variability for Turbuhaler compared to a pressurized metered dose inhaler. However, as Turbuhaler is easier for patients to use in a reproducible way than a pMDI the in vivo within and between subject dose variation has been found significantly lower for Turbuhaler compared to a pMDI. The in vivo variability is of much greater clinical importance.
Variability in lung deposition
The lung deposition from Turbuhaler® was much higher than that from pMDI, and the variability, both within and between subjects, was twice as great with pMDI as with Turbuhaler.
The in vivo variability in lung deposition of budesonide administered via Turbuhaler and fluticasone given via Diskus and pMDI has also been studied in healthy subjects and patients with asthma (2). Turbuhaler delivery resulted in significantly lower variability.
The higher dose variability of Diskus compared with Turbuhaler has also been seen in asthmatic children: 61.2% vs. 24.2% (3).
Variability in lung deposition from Turbuhaler and Diskus
Reference:
1. Borgström L et al.: Dose variation, within and between individuals, with different inhalation systems. Proceedings of Respiratory Drug Delivery V. Phoenix, Arizona, USA, April 28-May 2, 1996.
2. 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: A896.
3. Agertoft L, Pedersen S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993; 69:130-3.
Pulmicort Turbuhaler vs. Pulmicort pMDI
In the past clinical studies have investigated the relationship between Pulmicort Turbuhaler and Pulmicort pMDI and compared the efficacy over the dose range 200 µg to 800 µg twice daily (1-3). The combined data from these studies showed Pulmicort Turbuhaler to be significantly more effective than Pulmicort pMDI. In a further dose-response study (4), children with asthma had their doses of inhaled corticosteroids reduced until a relapse occurred. After treatment of the relapse they returned to their previous dose level and were randomized to receive either the original dose via pMDI or half the dose via Turbuhaler. Airway function improved in both groups to a similar degree showing that delivery via Turbuhaler was twice as effective.
Later it has been realized that the relation between different inhalers should be investigated by either of two methods:
1) dose-response studies with at least two doses of one of the formulations, and
2) dose-reduction studies where the same dose of both formulations is given at the start and the doses are then reduced until a relapse occurs.
Examples of this type of studies with an appropriate design are given below.
Reference:
1. Hetta L et al.: A comparative clinical study of inhaled budesonide delivered either via a pressurized metered dose inhaler or via Turbuhaler. Eur Respir J 1989; 2, Suppl 8: 832s.
2. Sinninghe Damsté HEJ et al.: A clinical comparison of inhaled budesonide administered either via a metered dose inhaler or via Turbuhaler. Eur Respir J 1989; 2, Suppl 8: 44s.
3. Engel T et al.: Clinical comparison of inhaled budesonide delivered either via pressurized metered dose inhaler or Turbuhaler. Allergy 1989; 44: 220-225.
4. Agertoft L, Pedersen S. Importance of the inhalation device on the effect of budesonide. Arch Dis Child 1993; 69: 130-133.
Pulmicort Turbuhaler vs. BDP pMDI
Comparison between two different inhaled corticosteroids delivered via different devices can be performed either as dose-response studies with at least two doses of one of the products, or as dose reduction studies. An example of the first mentioned is given here (1).
A study comparing 200 µg and 800 µg of Pulmicort Turbuhaler with 400 µg of beclomethasone dipropionate (BDP) pMDI showed no difference between the low dose Pulmicort and the twice as high dose of BDP (Fig.1). A firm conclusion about the equiefficacy of these two treatments can be drawn, as the 800 µg Pulmicort Turbuhaler dose was significantly superior compared to the two other treatments. Pulmicort 200 µg and BDP 400 µg were thus compared on the steep part of the dose-response curve where comparisons have to be made. If in this study population a difference had existed between 200 µg Pulmicort Turbuhaler and 400 µg BDP pMDI this had been detected.
Comparison between budesonide Turbuhaler and BDP pMDI
The adult patients entering the trial had continuing symptoms of asthma despite prior treatment with BDP (200 µg b.i.d. by pMDI). After a 2-week run-in period on this treatment, they were randomized to receive the same treatment, or budesonide (Pulmicort Turbuhaler), 100 µg b.i.d. or 400 µg b.i.d., for 6 weeks. Pulmicort Turbuhaler, 100 µg b.i.d., was at least as effective as BDP, 200 µg b.i.d. Pulmicort Turbuhaler, 400 µg b.i.d., was significantly more effective than both the other treatments.
Reference:
1. Miyamoto T et al.: Efficacy of budesonide Turbuhaler compared with beclomethasone dipropionate pMDI in Japanese patients with moderately persistent asthma. Respirology 2001; 6: 27-35.
Pulmicort Turbuhaler vs. fluticasone propionate Diskhaler and Diskus
The two most widely used inhaled corticosteroids worldwide are Pulmicort Turbuhaler and fluticasone propionate inhaled via DiskhalerTMr or DiskusTM (AccuhalerTM). The deposition figures for Diskus and Diskhaler are around 15% (1).
Compared with fluticasone inhaled via Diskus, Pulmicort Turbuhaler has a four times higher lung deposition in children (2)
Below two examples are given of the other acceptable comparative study design - the dose reduction study design.
In a study in 217 children already established on Pulmicort pMDI with a large volume spacer, the doses were reduced until a relapse occurred (3). After a 2-week run-in period the children were thereafter randomized to receive half the dose of either Pulmicort Turbuhaler or fluticasone propionate (FP) delivered via Diskhaler. The dose was further reduced at each 5-week visit if their asthma was adequately controlled. The minimal effective dose was the primary outcome measure. There was no significant difference between the two treatments showing that µg per µg Pulmicort Turbuhaler and FP Diskhaler are equally effective. The mean minimal effective doses were 212 µg per day of Pulmicort Turbuhaler and 198 µg of fluticasone Diskhaler. There was no statistically significant difference between the treatments.
Similar results have been shown in adults with asthma (4). In a double-blind dose reduction study 197 patients were stabilized in their asthma on 2000 µg of BDP. They were then randomized to receive 800 µg of Pulmicort Turbuhaler or fluticasone Diskus and the dose was halved at 5-week intervals if asthma control was maintained. The median minimal effective dose was 400 µg in both groups and there was no apparent difference in the distribution of doses between the groups.
Dose reduction study comparing Pulmicort Turbuhaler and fluticasone Diskhaler
On entry into the study, the patients were already established on budesonide, 200 or 400 µg/day, given via a large volume spacer (Nebuhaler®). After a 2-week run-in, patients were randomised to receive half the dose of one of the trial medications, and the dose was further reduced at each 5-week review if their asthma was adequately controlled (Agertoft and Pedersen, 1997). The minimal effective dose was the primary outcome measure.
Minimal effective dose of Pulmicort Turbuhaler and fluticasone Diskhaler
Minimal effective doses in a Danish comparative study of budesonide (Pulmicort) Turbuhaler and fluticasone Diskhaler® in childhood asthma. There was no significant difference in minimum dose between the two treatments, 198 µg for Pulmicort Turbuhaler and 212 µg for fluticasone Diskhaler.
Reference:
1. Thorsson L et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. Br J Clin Pharmacol 1997; 43: 155-161.
2. Agertoft L, Pedersen S. Lung deposition and systemic availability of fluticasone Diskus and budesonide Turbuhaler in children. Am J Respir Crit Care Med 2003; 168: 779-782.
3.Agertoft L, Pedersen S. A randomized double-blind dose reduction study to compare minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997; 99: 773-780.
4. Kuna P et al. A randomized, double-blind, double-dummy, parallel-group, multicenter, dose-reduction trial of the minimal effective dose of budesonide and fluticasone dry-powder inhalers in adults with mild to moderate asthma. Clin Ther 2003; 25: 2182-97.
The importance of therapeutic index
The dose-response curves for clinical efficacy and systemic activity/risk for side effects with inhaled corticosteroids are different.
All inhaled steroids can be equally effective as long as risk of side effects is not considered. Great differences exist between inhaled corticosteroids in their ability to give rise to systemic glucocorticoid activity. Compared with Pulmicort the more lipophilic steroid, fluticasone propionate, has a greater ability to cause systemic glucocorticoid activity, which may or may not depending on dose, result in systemic side-effects. The balance between wanted and unwanted effects must therefore always be considered. This can be expressed as a therapeutic ratio or therapeutic index (1,2). An extensive documentation has shown that Pulmicort Turbuhaler has a very favourable therapeutic ratio.
Therapeutic ratios of inhaled corticosteroids
Clinical and systemic potencies, and therapeutic index, of Pulmicort, beclomethasone dipropionate (BDP) and fluticasone propionate, delivered via pMDI or dry powder inhaler (DPI; Pulmicort via Turbuhaler, fluticasone via Diskhaler™). If all other considerations are equal, the preparation with the highest therapeutic index should provide the best balance between efficacy and safety.
Reference:
1. Pedersen S, O´Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997; 39, Suppl 52: 1-34.
2. Barnes PJ et al.: Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998; 157 (3 part 2): S1-S53.
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