Am. J. Respir. Crit. Care Med.,
Volume 163, Number 5, April 2001, 1279-1279
LUNG DEPOSITION OF INHALED DRUGS INCREASES
WITH AGE?
To the Editor :
Anhoj and colleagues (1) elegantly showed that plasma concentrations of
budesonide following inhalation from a metered dose inhaler (MDI) with valved
aerosol holding chamber (VHC) are similar between adults and children (irrespective of age). On the basis of these observations they went on to suggest that
this reflects a similar (per weight or per body surface area) lung dose and therefore, from a safety perspective, children and adults can use the same nominal
dose of budesonide. We believe that there are flaws in this argument.
Dosage recommendations, particularly with inhaled corticosteroids
(ICS), should take into account not only safety, but efficacy as well. The
present study provides no efficacy data. Efficacy clearly depends upon lung
dose, so should it be inferred that efficacy will also be similar? However, the
plasma concentration does not necessarily reflect only the lung dose, particularly if DPIs are used or MDIs without a particle size-selective aerosol holding chamber. It is only under the specific conditions of this particular study
that budesonide would have a "negligible" bioavailability due to nonlung absorption. Depending upon the efficiency of the MDI accessory device for removing the large drug particles (spacers remove only about 50% of the
oropharyngeal and laryngeal dose in contrast to VHCs that remove about
90% of the upper respiratory tract (URT) and 75% of the total body dose
[2]), the oropharyngeal, and GI absorption and contribution to plasma concentration can amount to 10-15% (3). Particularly in young children and infants breathing through a face mask, nasal absorption may be significantly more with up to 30% bioavailability (4)!
Moreover, age is an important determinant of the relative magnitude of
URT and lower respiratory tract (LRT) deposition. Younger children have
relatively more deposition in the URT than LRT and this ratio changes after
the age of approximately 2.5 years (5). There is an age difference also from a
pharmacokinetic perspective. Compared to adults, greater clearance rates
and a shorter plasma half-life have been found in children, suggesting an increase in the ratio between local and systemic side effects (6). As no attempt
was made in this study to account for the various nonpulmonary sources of
systemic absorption, the concentrations in plasma have little predictive therapeutic relevance. Thus it is difficult to draw conclusions about the therapeutic ratio, the most important factor in dosing recommendations. For therapy
with ICS in controlled asthmatics, there is no effective substitute for titration
to a minimum maintenance dose, thus optimizing both safety and efficacy.
Israel
Amirav
Sieff Hospital, Safed, Israel
Michael T.
Newhouse
McMaster University, Hamilton, Ontario, Canada
1.
Anhoj JA,
Thorsson L,
Bisgaard H.
Lung deposition of inhaled drugs increases with age.
Am J Respir Crit Care Med
2000;
162:
1819-1822
[Abstract/Free Full Text].
2.
Dolovich M,
Ruffin R,
Corr D,
Newhouse MT.
Clinical evaluation of the
aerochamber: A simple demand inhalation MDI aerosol delivery device.
Chest
1983;
84:
36-41
[Abstract/Free Full Text].
3.
Ryrfeldt A,
Edsbacker S,
Pauwels R.
Kinetics of the epimeric glucocorticoid budesonide.
Clin Pharmacol Ther
1984;
35:
525-530
[Medline].
4.
Allen DB. Systemic effects of intranasal steroids: an endocrinologist's
perspective. J Allergy Clin Immunol 2000;106(4 Suppl):179-190.
5.
Wildhaber JH,
Dore ND,
Wilson JM,
Devadason SG,
LeSouef PN.
Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler
with holding chamber? In vivo comparison of lung deposition in children.
J Pediatr
1999;
135:
28-33
[Medline].
6.
Pedersen S,
Steffensen G,
Ekman I,
Tonnesson M,
Borga O.
Pharmacokinetics of budesonide in children with asthma.
Eur J Clin Pharmacol
1987;
31:
579-582
[Medline].
From the Authors:
The comments from Drs. Amirav and Newhouse allow us to reiterate the
surprising findings in our recent study on the age-dependency of lung dose
(1). We found that plasma concentration of drug was proportional to body
size after inhalation of a fixed dose of aerosol. It is clearly emphasized in our
paper that this finding can only be extrapolated to other devices where dose
delivered is stable and independent of the age of the patient.
Because plasma concentrations were similar in young children with a
smaller volume of distribution and in adults with a larger volume of distribution, it is clear that a smaller dose had been absorbed to the circulation in the
young child. How could the dose of drug that reaches the plasma have been
reduced in young children? Any dose deposited in the lungs is absorbed almost completely. Any dose passing to the GI tract undergoes extensive metabolism (probably 90%) in the liver before it reaches the systemic circulation. It is therefore our interpretation that the reduced systemic dose reflects
reduced lung dose in proportion to body size. Drs. Amirav and Newhouse do
not present an alternative explanation.
Lung dose is determinant of efficacy and risk of systemic side effects. Yet
Drs. Amirav and Newhouse question the relevance of systemic steroid dose
for dose decision and ask for efficacy data and therapeutic ratio. Unfortunately, this is beside the point. We have studied the dose that becomes systemically available after inhalation of a steroid. By tradition, pediatricians reduce the steroid dose in younger children to avoid risk of increased systemic
exposure, as we are concerned not to cause side effects. This tradition has
been based on the belief that an aerosol passes to the lung independent of
the size of the child. However, the present finding reveals that such age-dependent dose titration may not be required, as there seems to be an age-dependent change in lung dose. This is surprising, and needs confirmation.
Hans
Bisgaard,
and
Jacob
Anhoi
Copenhagen University Hospital, Copenhagen, Denmark
Lars
Thorsson
AstraZeneca, R&O Lund, Sweden
1.
Anhoj JA,
Thorsson L,
Bisgaard H.
Lung deposition of inhaled drugs increases with age.
Am J Respir Crit Care Med
2000;
162:
1819-1822
.
