| 1. 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 DiskusTM
or DiskhalerTM 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
Lung
dose and suppression of plasma cortisol after repeated administration
(1000 µg twice daily for 7 days) of budesonide Turbuhaler,
fluticasone Diskus and fluticasone pMDI (4). Lung deposition with
budesonide Turbuhaler was approximately three-fold greater than with
fluticasone Diskus. Despite this higher pulmonary bioavailability,
however, the systemic effect of the two preparations was similar,
indicating a higher degree of systemic bioavailability with
fluticasone Diskus.
References:
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.
|
| 2. 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).
References:
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.
Variability
in lung deposition from Turbuhaler and Diskus
|
| 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.
References:
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
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.
|
| 4. 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.
|
| 5. 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.
References:
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.
|
| 6. 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
DiskhalerTM). If all other
considerations are equal, the preparation with the highest
therapeutic index should provide the best balance between efficacy
and safety
References:
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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