CURRICULUM VITAE __________________________________________________________________________________________ FULL NAME AND DEGREE/S: EDUCATION: Institution ACADEMIC APPOINTMENTS: 1995-1996 Research Assistant, M .S. Swaminathan Research Foundation, India 1996-1999 Teaching Assistant, School of Dietetics and Human Nutrition, McGill University, Canada 1999-2000 Res
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Www2.imm.dtu.dkArch Dis Child 1999;80:241–247
Systemic availability and pharmacokinetics ofnebulised budesonide in preschool children L Agertoft, A Andersen, E Weibull, S Pedersen Abstract
patient to patient, the average daily nominal Aim—To evaluate the systemic availability
dose being 1 mg.2 3 Considering the ages and and basic pharmacokinetic parameters of
body weights of preschool children, such a dose budesonide after nebulisation and intra-
seems quite high compared with the recom- venous administration in preschool chil-
mendations for adults and the dose required dren with chronic asthma.
when a pressurised metered dose inhaler with a Methods—Plasma
budesonide. For these reasons some paediatri- hours after an intravenous infusion of
cians have raised safety concerns about neb- 125 µg budesonide. The children then
ulised budesonide treatment. However, be- inhaled a nominal dose of 1 mg budeso-
nide through the mouthpiece of a Pari LC
adults in airway calibre and anatomy of the Jet Plus nebuliser connected to a Pari
upper airways, the inspiratory air flow dynam- Master compressor, and the plasma con-
ics of children might be quite diVerent from centrations of budesonide were measured
those of adults. Therefore, conclusions from for another six hours. The amount of
budesonide inhaled by the patient (“dose
systemic bioavailability of inhaled budesonide to subject”) was determined by subtract-
should be extrapolated to young children with ing from the amount of budesonide put
great caution. Indeed, nothing is known about into the nebuliser, the amount remaining
the pharmacokinetics of budesonide in pre- in the nebuliser after nebulisation, the
school children or the percentage of the nomi- amount emitted to the ambient air (filter),
nal dose that becomes systemically available and the amount found in the mouth
The aim of our study was to assess the abso- Results—Ten patients aged 3 to 6 years
lute systemic availability and basic pharma- completed both the intravenous and the
cokinetic parameters of budesonide given as a inhaled treatment. The mean dose to sub-
nebulised suspension in young children via a ject was 23% of the nominal dose. The sys-
widely used jet nebuliser, Pari LC Jet Plus con- availability
estimated to be 6.1% of the nominal dose
GmbH, Starnberg, Germany). In addition, the (95% confidence intervals (CI), 4.6% to
method of assessing inhaled dose and nebuliser 8.1%) or 26.3% of the dose to subject (95%
output in vivo by inserting filters to the CI, 20.3% to 34.1%). Budesonide clearance
inspiratory and expiratory outlets was evalu- was 0.54 l/min (95% CI, 0.46 to 0.62),
steady state volume of distribution 55 li-
tres (95% CI, 45 to 68), and the terminal
Patients and methods
half life was 2.3 hours (95% CI, 2.0 to 2.6).
Children aged 3 to 6 years with chronic asthma Conclusions—Approximately 6% of the
nominal dose (26% of the dose to subject)
budesonide from a pressurised metered dose reached the systemic circulation of young
inhaler with a spacer were included in the children after inhalation of nebulised
study. All patients had to demonstrate a correct budesonide. This is about half the sys-
inhalation technique with the Pari LC Jet Plus temic availability found in healthy adults
nebuliser equipped with a mouthpiece. The using the same nebuliser.
study was performed in accordance with the (Arch Dis Child 1999;80:241–247)
Declaration of Helsinki. Written and verbal Department of
parents of all children before any study related Hospital, DK-6000
The design was an open, single centre, phar- Inhaled corticosteroids are normally adminis- macokinetic study consisting of three visits to tered to preschool children by a pressurised the clinic. Visits 1 and 2 were separated by one metered dose inhaler plus a spacer with a valve to two weeks and visits 2 and 3 by no more than Astra Draco AB, PO
system or by a jet nebuliser. Only a few clinical one week. Two treatments were given: an intra- Box 34, S-221 00, Lund,
dose finding studies have been conducted with venous infusion of budesonide and a single budesonide delivered by nebuliser in these age inhaled dose of nebulised budesonide, both at groups.1 2 These studies found that the mini- visit 3. A semi-simultaneous design was used— mum eVective dose required to control the dis- that is, the two administrations were given in a fixed order with the inhaled dose given three severe asthma symptoms varied markedly from hours after the start of the infusion.
Agertoft, Andersen, Weibull, Pedersen The patients rinsed their mouths twice with The patient was instructed and trained in the 10 ml tap water directly after nebulisation and correct use of the nebuliser using placebo.
the rinsing water was collected for later analy- Correct use was considered to be tidal breath- sis for budesonide content. The budesonide ing without any pauses or leakage around the content in the intravenous solution, on the mouthpiece. A nose clip was worn during the expiratory filter, in the ampoule, in the inhalation. When the child had a correct inha- nebuliser, and in the mouth rinsing water was lation technique, he/she was given a nebuliser with a compressor and placebo for further method. Rigorous precautions were taken to training at home before the next visit.
avoid contamination of the plasma sampleswith budesonide from the nebulisation.
Blood samples (4–5 ml) were drawn before The patient’s inhalation technique was checked the start of infusion (0), at the end of infusion (placebo). This was followed by an inhalation with filters (filter inhalation): an unused Pari minutes after the start of infusion and at 180 LC Jet Plus nebuliser connected to a Pari Mas- minutes after the start of infusion (immediately ter compressor was equipped with an inspira- before inhalation). In addition, samples were tory filter between the nebuliser and the taken at the end of inhalation and at 20, 40, 80, mouthpiece and an expiratory filter attached to 160, 240, 330, and 360 minutes after the start the expiratory outlet. The amount of drug of inhalation. The plasma samples were stored deposited on the inspiratory filter is assumed to frozen until analysis for budesonide content.
be a measure of the amount of drug inhaled by The total sampling time was nine hours and the the patient while the amount on the expiratory total blood volume taken from each child was filter is considered to be a measure of the amount of drug emitted to the ambient air Venflon inserted for intravenous administra- tion, the absolute systemic availability of suspension and the patient inhaled as de- scribed under visit 1. Nebulisation time was ever, the inhalation and subsequent blood five minutes. The nebuliser was tapped gently sampling could still be carried out.
during nebulisation and it was ensured that the The plasma concentration of the sum of the patient had a correct inhalation technique. The nebuliser was weighed before and after charg- determined by a liquid chromatography plus ing and after nebulisation. The filters were mass spectrometry method. The lower limit of stored in dark plastic bags at room temperature quantification was 0.025 nmol/l. The between until analysis for budesonide content by a assay coeYcient of variation (CV) in control samples run in parallel with the study samples At the end of the visit, the nebuliser was dis- mantled, thoroughly washed with ethanol, left to dry, and then reassembled, ready to be usedagain by the same patient at visit 3.
IN VITRO CHARACTERISTICS OF THE NEBULISERPari LC Jet Plus delivers a dose of budesonide, measured in vitro with filters, of about 23% of Inhaled budesonide was discontinued two days before visit 3. On arrival at the clinic, indwell- 0.5 mg/ml of budesonide. The droplet size, ing catheters (Venflon; Becton Dickinson BOC Malvern Mastersizer X (Malvern, Worcester- serted in both arms after pretreatment with shire, UK), is 5 µm. When charged with 2 ml of budesonide suspension, the nebuliser normally Södertälje, Sweden). One arm was used for runs to dryness within five minutes.
intravenous infusion of budesonide and theother for blood sampling.
A budesonide solution (20 ml of 6.25 µg/ml, total dose 125 µg) was infused manually at a The dose inhaled by the patient during nebuli- constant rate over 10 minutes. The infusion sation was assessed at visits 2 and 3.
was followed by an injection of 5 ml sterilesaline to rinse the catheter before it wasremoved. A sample of the infused budesonide solution was frozen for later analysis of The amount of budesonide recovered from the budesonide concentration. The syringe was inspiratory (I) and expiratory (E) filters was weighed before and after infusion to obtain the used to estimate the inhaled dose, the total output from the nebuliser (I + E), and the measured concentration and the density of the inhaled dose in percentage of the total output infused solution, was used to calculate the Three hours after the start of the infusion, The “dose to subject” was calculated by exactly the same way as during filter inhalation subtracting from the assayed batch dose the at visit 2, except that an inspiratory filter was sum of the amounts of budesonide recovered not used and the nebuliser was not weighed.
Nebulised budesonide in preschool children Measurement of inhaled budesonide dose, budesonide dose on expiratory filter, and inhaled dose in % of total output in 12 preschool children by two diVerent methods (filter and drug inhalation) G mean; geometric mean; CV, coeYcient of variation.
expiratory filter, the nebuliser with mouthpiece ject), and F (systemic bioavailability after inha- and connecting tubes, and the mouth rinsing lation in percentage of nominal dose).
In the secondary analysis, the last observable The inhaled dose was calculated as the sum phase after the intravenous administration was of the dose to subject and the amount of drug assumed to be the terminal elimination phase recovered from the mouth rinsing water.
after an intravenous dose (diVerent half lives) The total output from the nebuliser was cal- culated as dose to subject plus the amounts of assumption. This may be interpreted as an budesonide recovered from the mouth rinsing absorption rate limited elimination for neb- ulised budesonide (a flip flop phenomenon).
Doses and ratios between doses or amounts This analysis might also provide an upper limit from filter and drug inhalations were described for the systemic availability if there is no flip with the geometric mean and 95% confidence flop, but the terminal phase after intravenous limits using the t distribution. The nominal administration starts later than three hours dose was defined as the dose written on the PARAMETRIC PHARMACOKINETIC ANALYSISA pharmacokinetic model was fitted to the NON-PARAMETRIC PHARMACOKINETIC ANALYSESBecause the half life of the last observable plasma concentration data using a non-linear phase after intravenous administration was mixed eVects model approach. The population found to be shorter than the terminal half life parameters were estimated using the Vonesh- seen after inhalation, diVerent analyses based Carter algorithm4 and approximate 95% confi- were possible. In the primary analysis, the ter- minal half life after intravenous administration the intravenous administration because two was assumed to be identical to the terminal half clear phases were seen after the intravenous life seen after inhalation (identical half lives).
dose and a third, slower phase, was seen after Thus, the terminal elimination rate constant, k was estimated from the plasma concentra- tions after inhalation by mathematically fitting a straight line to the last plasma measurements included in our study. Ten patients completed regression. The intravenous and the inhalation both intravenous and inhaled treatment. One curves were then separated from each other by child received only inhaled treatment because assuming that the terminal phase for the intra- of problems with the intravenous administra- venous dose was reached when the inhalation tion. Two children were withdrawn because of started, three hours after the intravenous dose.
lack of cooperation and problems with blood sampling, but the inhalation data from one of intravenous curve were subtracted from the measured concentrations after inhalation to children for comparison between filter and drug inhalation. The mean age of the eight The pharmacokinetic parameters calculated budesonide administrations on visit 3 was 4.7 using non-parametric methods were described years (range, 3–6). Their mean height was with means and 95% confidence limits for the 109 cm (range, 95.5–121.0); mean weight was mean calculated using the t distribution. Geo- 18.4 kg (range, 15.0–25.5). No adverse events metric means were used for T1⁄ (terminal half life), Cl (total clearance), V (volume of distri- bution during terminal phase), V (volume of A mean of 246 µg, or 25% of the nominal dose, bioavailability in percentage of dose to sub- was recovered from the inspiratory filter. This Agertoft, Andersen, Weibull, Pedersen Individual (thin lines) and estimated mean (bold and bold dashed lines) budesonide plasma Correlation between estimates of inhaled dose concentration curves (log scale) in 10 preschool children (% of nominal) from filter inhalation and drug inhalation after intravenous infusion of 117 µg budesonide and of budesonide from a Pari LC Jet Plus nebuliser in 12 inhalation of 1000 µg budesonide from a Pari LC Jet Plus nebuliser. Mean curve was obtained from the parametricanalysis with a three exponential model. corresponds to 57% of the total nebuliser out-put, which was 428 µg, or 43% of the nominal on the expiratory filter after filter inhalation.
dose. The between-patient variation in these Thus, the lower total output after filter inhala- tion was mainly a result of a lower amount on the expiratory filter after this inhalation.
The total output from the nebuliser (inhaled dose + drug on expiratory filter) was 471 µg, or 47% of the nominal dose. The mean inhaled 117 µg) and the dose to subject ranged from dose (dose to subject + amount in mouth rins- 192 to 273 µg (geometric mean, 232 µg). All ing water) was 236 µg or 24% of the nominal plasma samples after drug administration had dose (50% of total nebuliser output). The concentrations above the limit of quantifica- tion. The individual plasma profiles after the nominal dose). The between patient variation consistent in shape (fig 2). The half life of the magnitude as for the corresponding estimates last observable phase after intravenous admin- from the filter inhalation (table 1).
istration was shorter than the terminal half lifeseen after inhalation for all patients.
parameters and 95% confidence limits calcu- In general, there was good agreement between lated from the primary and secondary non- the methods of assessing the inhaled dose dur- parametric analyses and from the three expo- ing nebulisation (table 1; fig 1). The mean ratio between the amount on the inspiratory filter availability in percentage of nominal dose or and inhaled dose after drug inhalation was percentage of dose to subject were very similar in the three analyses, whereas half lives and volumes of distribution were, as expected, nebuliser after filter and drug inhalation was somewhat lower in the non-parametric analysis significantly lower total output after filter inha-lation. The mean ratio between the amounts found on the expiratory filters after filter and To enable comparison of clearance and vol- umes of distribution with the values obtained 84%); there was a significantly lower amount in adults in a previous study,5 these parameters Estimated pharmacokinetic parameters of budesonide in 10 preschool children by: a non-parametric evaluation assuming identical terminal half lives after intravenous administration and inhalation; a non-parametric evaluationassuming diVerent terminal half lives after intravenous administration and inhalation; and by a three exponential model Cl, total clearance; V , volume of distribution in terminal phase; V , volume of distribution at steady state; F ability in % of dose to subject; F, systemic bioavailability in % of nominal dose.
Nebulised budesonide in preschool children Scaled pharmacokinetic parameters of budesonide in 10 preschool children estimated in a non-parametric evaluation assuming identical or diVerent terminal half lives after intravenous infusion and inhalation of budesonide Key messages
reaches the systemic circulation of young children after inhalation from a Pari LCJet Plus nebuliser Cl, total clearance; V , volume of distribution in terminal phase; V , volume of distribution at were expressed per kg body weight (table 3). In addition, clearance was scaled to a 70 kg subject by using weight0.75 as an adjustment + The low systemic availability in combina- factor instead of simply scaling by weight1.0, 6.
Volumes were scaled to a 70 kg subject by weight1.0 only. Table 3 gives a summary of the parametric analysis, assuming identical termi- nal half lives after infusion and inhalation. In addition, the parameters from non-parametric analysis assuming diVerent terminal half lives after intravenous administration and inhalation are given for comparison. No age dependence + A filter inhalation accurately assesses the parameters or inhaled dose, as assessed by individual patient it is only a crudesurrogate marker of the systemic avail-ability and dose of budesonide deposited Discussion
Our study provided important information
about the systemic availability of budesonide inyoung children after nebulisation. A systemicavailability around 6% is about half the value previously found in healthy adults using the deposited in the intrapulmonary airways by personal communication, 1996) or with a Spira inhalation.8 10 Therefore, the estimate of lung synchroniser (15%).7 If the systemic availability deposition in our study is probably close to the is related to the dose to subject instead, the dif- maximum achievable with the nebuliser used.
ference between children and adults seems The use of a face mask is likely to reduce the even more pronounced: 26% in children and therapeutic ratio (clinical eVect/systemic eVect ratio), whereas its influence on the total niser) in adults. Lung deposition could be esti- mated to be around 18% of dose to subject in our children. This should be compared with between the various pharmacokinetic param- estimated lung depositions of 58% (synchro- eters or inhaled dose and age, perhaps because niser) and 70% (no synchroniser) in the two the age range was too narrow. No other studies adult studies. Furthermore, the deposition in have assessed the possible age dependency of the oropharynx was estimated to be ∼82% of the various pharmacokinetic parameters of dose to subject in young children compared dependent lung deposition or drug delivery to synchroniser) in adults. This indicates a very the patient with various inhalation devices,11 12 diVerent deposition pattern in young children whereas others have found lung deposition to and adults, which is probably caused by the smaller dimensions of the oropharynx and lar- ynx in young children. These findings empha- budesonide in children are sparse, so it is diY- sise that conclusions from adult deposition cult to make direct comparisons of our data studies cannot be extrapolated to children. The with the findings of others. In our study, mean studies must be conducted in the age groups in clearance was estimated to be around 30 ml/ which the inhaler is going to be used.
min/kg, which is ∼50% higher than in healthy adults.5 This is in agreement with the findings results are discussed it must be remembered in older children.13 Volume of distribution/kg that the standardised and very controlled study body weight in steady state was about 15% conditions diVered greatly from the day to day higher than in adults,5 whereas the terminal clinical treatment situation. In day to day treat- half life after inhalation (2.3 hours) seemed to ment, the variability in inhaled dose is likely to be within the range of the terminal half life after be higher and the lung deposition lower.8 9 In intravenous administration in adults. In con- these age groups, use of a face mask is often trast, the half life after intravenous administra- associated with inhalation through the nose, tion (1.2 hours) was much shorter than in Agertoft, Andersen, Weibull, Pedersen adults. This could be a result of the study size. Thus, these results do not support scaling of the dose in mg/kg to limit systemic eVects.
followed for only three hours, and thus might Nebulisation time was fixed to five minutes have been truncated before the terminal phase because in vitro tests before the study showed was entered. These findings emphasise that this to be long enough to run the nebulisers to comparisons between studies with diVerent dryness. A fixed time end point also avoided sampling times and designs should be made the diYcult judgment of “dryness” from the with caution, because the results may vary with sputtering sound of the nebuliser. In our study, 70% of the charged weight was lost during A semi-simultaneous design was preferred to nebulisation, suggesting that a nebulisation administrations on separate days because of the time of five minutes is suYcient to run the reduction in intra-individual variation,14 a nebulisers to dryness in vivo when a 2 ml lower number of vein punctures, fewer blood charge is used. Therefore, we do not believe samples, a shorter sampling period, and an that this aVected the conclusions of the study.
Filter studies are often used as surrogates for measurable plasma concentrations. It has been determination of the inhaled dose and lung shown previously that the systemic availability deposition of drug.11 12 16–19 However, the filter of terbutaline could be estimated as accurately method has not yet been validated in young and precisely with this method as with the children with asthma. In our study, there was stable isotope method.15 In our study, however, excellent agreement between the two ways of the diVerent half lives seen after intravenous assessing the inhaled dose. This is in accord- administration and inhalation made several ance with the results of a study in adults interpretations possible. Either the terminal assessing deposition of radiolabelled pentami- half lives after intravenous administration and dine in the intrapulmonary airways.20 21 How- inhalation are identical and the intravenous ever, the poor correlation between inhaled dose curve is truncated before entering the terminal and systemic availability in our study indicates phase, or there is a diVerence in half lives as a that important factors other than inhaled dose result of an absorption rate limited elimination influence the deposition of nebulised budeso- of inhaled drug. An absorption rate limited nide in the intrapulmonary airways. Our study elimination of inhaled budesonide was consid- does not allow any conclusion about which ered an unlikely explanation for the diVerence in half lives, because no such observations have The amount of drug on the expiratory filter been made in adult pharmacokinetic studies and total drug output were slightly lower for with Turbuhaler or pressurised metered dose the filter inhalation compared with the drug inhalers.5 However, the estimates of systemic inhalation. The only diVerence between the availability and clearance from all three diVer- two experimental set ups was the absence of an inspiratory filter during drug inhalation, sug- mean availabilities in the range of 6–8% and gesting that the introduction of an inspiratory filter might have caused the diVerence. This suggests that our conclusions are reasonably suggestion is in accordance with the findings of robust and not heavily dependent upon the other studies.3 16 22 23 The reason for this change is not clear. It might be a result of the increased Young children often use nebulised doses of dead space in the nebuliser or to the somewhat budesonide that are in the same dose range as higher resistance caused by the filter. This those used by adults. This causes great concern should be remembered when the findings of among many paediatricians and it is often sug- gested that nebulised drugs should be scaled toyoung children by dosing in mg/kg to reducethe risk of systemic side e 1 Ilangovan P, Pedersen S, Godfrey S, et al. Treatment of severe steroid dependent preschool asthma with nebulised budesonide suspension. Arch Dis Child 1993;68:356–9.
2 Wennergren G, Nordvall SL, Hedlin G, et al. Nebulized budesonide for the treatment of moderate to severe asthma in infants and toddlers. Acta Paediatr 1996;85:183–9.
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Systemic availability and pharmacokinetics of
nebulised budesonide in preschool children
L Agertoft, A Andersen, E Weibull, et al.
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