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PHARMACOKINETICS

Pharmacokinetics of Budesonide and Formoterol Administered Via 1 Pressurized Metered-Dose Inhaler in Patients With Asthma and COPD

Ann Tronde, PhD, Michael Gillen, BS (Pharm), Lars Borgström, PhD, Jan Lötvall, MD, PhD and Jaro Ankerst, MD, PhD

From AstraZeneca R&D Lund, Lund, Sweden (Dr Tronde, Dr Borgström); AstraZeneca, Wilmington, Delaware (Mr Gillen); Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden (Dr Lötvall); and Research Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden (Dr Ankerst).

Address for reprints: Ann Tronde, PhD, AstraZeneca R&D Lund, SE-221 87, Lund, Sweden; e-mail: Ann.Tronde{at}astrazeneca.com.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (Cmax) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and Cmax were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and Cmax were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and Cmax were similar and formoterol AUC and Cmax 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Key Words: Pharmacokinetics • budesonide • formoterol • budesonide/formoterol pMDI • combination inhaler

Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β2-adrenergic agonist (LABA) is recommended first-line therapy for adolescents and adults with moderate to severe persistent asthma.1 In patients with moderate (stage 2) to very severe (stage 4) chronic obstructive pulmonary disease (COPD), regular LABA use is recommended in addition to as-needed short-acting β2-adrenergic agonist therapy.2 Regular ICS therapy also is recommended to decrease exacerbation frequency in patients with severe (stage 3) and very severe COPD who experience repeated exacerbations.2 Studies in patients with COPD have shown ICS/LABA combination therapy to be more effective than ICSs alone at reducing exacerbations and improving lung function.2-7

The ICS budesonide and the LABA formoterol have been studied extensively8,9 and are widely clinically used around the world. Budesonide and formoterol also have been combined in a dry powder inhaler (DPI) for use outside of the United States in adults and children with asthma and patients with COPD. Randomized, double-blind clinical studies have shown the combination of budesonide and formoterol in 1 DPI to be more effective than budesonide DPI alone and similar to the combination of budesonide and formoterol administered via separate inhalers in improving pulmonary function, controlling symptoms, and reducing reliever use in patients with asthma10-13 and in decreasing the risk of exacerbation in patients with COPD.3,7 These studies also demonstrate that no treatment-related differences exist in adverse events (AEs) or additional safety concerns after treatment with budesonide/formoterol DPI compared with the monocomponents and placebo3,7,10-12 and compared with the combination of budesonide and formoterol administered via separate inhalers.13

In addition to standard measures of clinical safety, the determination of pharmacokinetic parameters for inhaled asthma medications provides a more complete understanding of the potential for systemic side effects of these drugs. Drug formulation, as well as delivery device, can affect the pharmacokinetic profile of inhaled medications.14,15 Age, disease state, and the severity of the disease also may affect the pharmacokinetic parameters of asthma medications.16,17 Thus, consideration of these factors is important when evaluating new asthma medications.

The aim of the present investigation was to evaluate the systemic bioavailability of the recently introduced budesonide/formoterol pressurized metered-dose inhaler (pMDI) compared with the DPI formulations of the same substances and an experimental budesonide pMDI formulation. Asthmatic children and adults, as well as COPD patients, were included in the studies.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The investigation was divided into 3 separate studies. All treatments were administered in an open-label manner, and participants were trained to ensure correct use of inhalation devices. Actual doses and detailed study designs are given in Table I.


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  		Table I Clinical Study Designs

 
The inhalers used in the studies were as follows:

All study protocols were approved by institutional review boards (study 1: Regional Ethics Committee [Lund, Sweden]; studies 2 and 3: Arkansas Research Human Volunteers Research Committee [Little Rock, Arkansas]) for each of the clinical sites (study 1: Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital [Gothenburg, Sweden] and Research Department of Clinical Pharmacology, Lund University Hospital [Lund, Sweden]; studies 2 and 3: Arkansas Research Medical Testing [Little Rock, Arkansas]) and conducted in conformance with guidelines for the ethical treatment of human subjects, good clinical practice, and applicable local regulations. Written informed consent and, where appropriate, written assent were obtained before any study procedures were initiated.

Children and adults with asthma had a documented history of asthma for at least 6 months with a constant daily dose of ICS for at least 3 months before study entry. Adults had a prebronchodilator forced expiratory volume in 1 second (FEV1) of 60% to 90% predicted normal and reversibility of FEV1 of at least 12% and 0.20 L from baseline. Patients with COPD (restricted to those aged ≥40 years) had a clinical diagnosis of COPD for at least 2 years, with a prebronchodilator FEV1 of 20% to 70% predicted normal. Adult participants had a body mass index of 18 to 30 kg/m2, and children (6-11 years of age) were required to weigh at least 16 kg. The presence of any significant disease or disorder that, in the opinion of the investigator, might put the subject at risk, influence the results of the study, or affect his or her ability to participate in the study resulted in exclusion, as did the presence of a clinically significant abnormality in laboratory test results, physical examination findings, vital signs, or electrocardiogram monitoring. Women of childbearing age were to use an approved method of birth control, unless infertile.

Sample Collection
Blood samples for the analysis of budesonide and formoterol were collected predose and frequently after dosing until 24 hours in study 1, until 12 hours in study 2, and until 36 hours in study 3. Blood samples were collected into sodium-heparinized tubes and centrifuged at 1500 g for 10 minutes at room temperature. For budesonide, the plasma was transferred to cryotubes; for formoterol, the plasma was transferred to cryotubes containing citric acid. Samples were stored below –20°C before analysis.

Urine samples for the determination of unchanged formoterol were collected for analysis in studies 1 and 2 over 48-hour (0-24 and 24-48 hours) and 24-hour (0-12 and 12-24 hours) postdose periods, respectively. Urine sample time and weight were recorded, and samples were stored at –20°C before analysis.

Measurement of Budesonide and Formoterol Concentrations
Quantitative determination of budesonide (22RS epimers) was performed by TNO Nutrition and Food Research (Zeist, the Netherlands), and analysis of formoterol was performed by Quintiles AB Analytical Services (Uppsala, Sweden). The budesonide and formoterol assays were based on a combined method of liquid chromatography and mass spectrometry.

Budesonide and the internal standard (2H8-labeled analog of budesonide) were detected using negative ion multiple-reaction monitoring (MRM) of the transitions of the acetate adduct of budesonide (m/z: 489-357) and its internal standard (m/z: 497-357). The plasma method was validated over the concentration range 0.010 to 10 nmol/L, with a lower limit of quantification (LLOQ) of 0.01 nmol/L in studies 1 and 3 and of 0.02 nmol/L in study 2. The interassay repeatability was 2.4% to 13.0%, and the accuracy was within the range of –4.0% to 0.2%.

Formoterol and the internal standard (2H4-labeled analog of formoterol) were detected using electrospray (ESI) positive ion MRM of the following transitions m/z: 345.00 to 149.20 (formoterol) and 349.00 to 153.30 (internal standard). The plasma method was validated over the concentration range 5.00 to 1000 pmol/L with an LLOQ of 5.00 pmol/L. The interassay repeatability was 3.0% to 6.6%, and the accuracy was better than 8.4%. The urine method was validated over the concentration range 40.0 to 50 000 pmol/L with an LLOQ of 40.0 pmol/L using a 1.0-mL sample volume. The interassay repeatability was 5.0% to 11.1%, and the accuracy was better than 4.6%.

Calculation of Pharmacokinetic Parameters
Plasma concentrations of budesonide and formoterol were evaluated using standard nonparametric methods. Terminal elimination rates for budesonide and formoterol (kel) were estimated for each patient and treatment using linear regression analyses of the terminal decrease in plasma concentration versus time values. The following pharmacokinetic parameters were calculated: area under the curve (AUC) of plasma concentration versus time, calculated using the trapezoidal method; maximum plasma concentration (Cmax); time at which Cmax occurred (tmax); elimination half-life (t1/2), calculated as ln(2)/kel; and the fraction of the formoterol nominal delivered dose excreted unchanged in the urine 0 to 48 hours after administration (Fe0-48 h) in study 1 and 0 to 24 hours after administration (Fe0-24 h) in study 2. The latter parameter was calculated based on the amount of formoterol excreted unchanged in the urine, assuming a molecular weight of 420.45 g/mol.

Safety Variables
Safety and tolerability were based primarily on the incidence and severity of AEs collected using spontaneous patient/parent/guardian reports and standard questioning by the investigator or his or her personnel at each clinic visit.

Statistical Analyses
All studies were descriptive in nature, and sample sizes were based on variability observed in previous studies. Pharmacokinetic analyses in the 3 studies included data from all participants. Values for AUC, Cmax, t1/2, and Fe0-24 h/48 h were compared between treatments or patient groups using a multiplicative (ie, log-transformation) analysis of variance (ANOVA) model, with fixed factors of treatment, period, and patient. Comparisons between patients with asthma and those with COPD in study 3 were made using a multiplicative ANOVA model with treatment as the fixed factor. Mean treatment ratios and 90% confidence intervals were calculated from the models. The tmax was summarized descriptively.

Safety was evaluated for all patients who received at least 1 dose of study drug and who had available data after randomization or assignment. Adverse events were summarized descriptively.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patient demographics across the 3 studies are summarized in Table II.


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  		Table II Patient Demographics

 
Study 1: Pharmacokinetics of budesonide and formoterol when administered via budesonide/formoterol pMDI, budesonide pMDI, budesonide DPI, and formoterol DPI in adults with asthma. Budesonide pharmacokinetic variables and pairwise treatment comparisons are shown in Table III. After treatment with budesonide/formoterol pMDI or budesonide pMDI, mean budesonide AUC was approximately 30% lower and Cmax approximately 50% lower compared with treatment with budesonide DPI. The budesonide AUC was similar for budesonide/formoterol pMDI and budesonide pMDI (ratio, 98%), with the 90% confidence interval falling within the 80% to 125% established bioequivalence limits. However, Cmax was 24% higher with budesonide/formoterol pMDI than with budesonide pMDI. Estimated mean t1/2 values were similar among the treatments (ratios, 92% to 102%).


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  		Table III Comparison of Pharmacokinetic Parameters for Budesonide and Formoterol Administered Via Budesonide/Formoterol pMDI, Budesonide pMDI, Budesonide DPI, and Formoterol DPI in Patients With Asthma (Study 1)

 
The mean formoterol AUC value was 13% lower after treatment with budesonide/formoterol pMDI versus formoterol DPI. The mean formoterol Cmax and Fe0-48 h were lower (39% and 18%, respectively) after administration of budesonide/formoterol pMDI compared with formoterol DPI. On average, 7.80% of the formoterol dose was excreted unchanged in the urine 48 hours after treatment with budesonide/formoterol pMDI compared with 9.48% after treatment with formoterol DPI, resulting in a mean ratio of 82% for budesonide/formoterol pMDI versus formoterol DPI (Table III). Approximately 90% of the total amount of formoterol excreted unchanged in the urine was excreted during the first 24-hour interval after drug administration.

Study 2: Pharmacokinetics of budesonide and formoterol in children with asthma when administered via budesonide/formoterol pMDI and budesonide DPI + formoterol DPI. Pharmacokinetic parameters for budesonide and formoterol and treatment comparisons are shown in Table IV. Mean budesonide AUC and Cmax values were 27% and 41% lower, respectively, after administration of budesonide/formoterol pMDI compared with consecutive administration of budesonide DPI + formoterol DPI. However, the variability in these data was large, with coefficients of variation of 55% and 95% for budesonide/formoterol pMDI AUC and budesonide DPI + formoterol DPI AUC, respectively. Corresponding coefficients of variations for Cmax were 100% and 137%. Estimated t1/2 was slightly longer after treatment with budesonide/formoterol pMDI compared with budesonide DPI + formoterol DPI.


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  		Table IV Comparison of Pharmacokinetic Parameters of Budesonide and Formoterol Administered Via Budesonide/Formoterol pMDI or Budesonide DPI + Formoterol DPI in Children With Asthma (Study 2)

 
On average, 3.48% of the formoterol dose was excreted unchanged in the urine after treatment with budesonide/formoterol pMDI compared with 3.09% after treatment with budesonide DPI + formoterol DPI, resulting in a mean ratio of 113% for budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI (Table IV).

Study 3: Pharmacokinetics of budesonide and formoterol in adult patients with COPD or asthma when administered via budesonide/formoterol pMDI and budesonide pMDI + formoterol DPI. In COPD patients, mean budesonide AUC and Cmax values were nearly identical for both treatments (ratios, 97% and 104%, respectively, for budesonide/formoterol pMDI versus consecutive administration of budesonide pMDI + formoterol DPI; Table V). Estimated values for mean t1/2 were similar for the 2 treatments.


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  		Table V Comparison of Pharmacokinetic Parameters of Budesonide and Formoterol Administered Via Budesonide/Formoterol pMDI or Budesonide pMDI + Formoterol DPI in Adult Patients With COPD (Study 3)

 
Mean formoterol AUC was 18% higher after treatment with budesonide/formoterol pMDI compared with budesonide pMDI + formoterol DPI, and Cmax values were 22% higher for budesonide/formoterol pMDI (Table V). Estimated values for t1/2 were similar for the 2 treatments.

Comparison of budesonide pharmacokinetic parameters in patients with COPD versus asthma after administration of budesonide/formoterol pMDI showed a 12% higher mean AUC value for budesonide in patients with COPD, whereas mean Cmax was 10% lower for these patients compared with patients with asthma. Mean t1/2 values were longer in patients with COPD (5.27 hours) versus asthma patients (4.57 hours). Evaluation of formoterol pharmacokinetic parameters after administration of budesonide/formoterol pMDI showed a 15% and 12% higher mean AUC and Cmax value, respectively, in patients with COPD compared with patients with asthma. Estimated half-life values for formoterol were slightly longer in patients with COPD (9.23 hours) compared with patients with asthma (8.72 hours).

Safety and Tolerability
All treatments were well tolerated, and no new or unexpected safety findings were identified. No AEs were reported among children with asthma in study 2. The most common AEs in adult patients with asthma in study 1 were tremor, palpitations, and headache. In the adult asthma or COPD patients in study 3, the most common AEs were tremor, dizziness, and headache. All findings were consistent with expected high-dose β2-adrenergic agonist administration.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
For inhaled medication, it is not only the drug concentration at the effector site—in this case, the lung—that is of importance but also the concentration in the systemic circulation. Systemic exposure to drugs after inhalation is due to absorption directly through the lung, as well as gastrointestinal absorption of swallowed drug. Thus, for substances with a low systemic availability after oral intake and a negligible biotransformation in the lung after inhalation, such as budesonide and formoterol, the major portion of systemically available drug comes via the lung.18 For such drugs, the systemic exposure mainly reflects the lung exposure and eventually the exerted local clinical effects.19 Whether or not an observed lower systemic exposure is reflecting a significantly lower clinical effect in the lung is dependent on a number of factors, such as regional lung deposition, local site of action, lung retention, and where on the dose-response curve the doses have been given.

In the present clinical program, the actual head-to-head comparisons of budesonide/formoterol versus the monoproducts with regard to clinical efficacy and safety in adult and pediatric patients with asthma have been published elsewhere.20,21 In addition, a direct comparison of budesonide/formoterol pMDI with formoterol DPI demonstrated equivalent acute bronchodilatory effects across a dose range of 4.5 to 18 µg,22 despite the lower total systemic exposure demonstrated in these studies with budesonide/formoterol pMDI.

It is clear that higher drug concentrations in the systemic circulation increase the risk of unwanted side effects and decrease drug safety.23 These studies therefore focus on systemic bioavailability (ie, systemic exposure) after inhalation to allow an evaluation of the systemic safety of budesonide/formoterol pMDI in comparison with already marketed and clinically used formulations (except for the experimental budesonide HFA pMDI) of budesonide and formoterol.

Our intention was to perform these studies in a variety of patient groups, including adults and children with asthma and adults with COPD, because age and disease status have been reported to affect the pharmacokinetics of asthma medications.16,17 In all of the studies, drug products were administered at doses high enough to maintain measurable plasma concentrations of budesonide and formoterol over a timeframe that was sufficient to reliably estimate pharmacokinetic parameters.

Budesonide
Results of a previous study reported by Martin et al24 demonstrated the importance of comparing the pharmacokinetics of drugs delivered through different devices. In that study, greater lung exposure, as well as systemic effects, was observed with the ICS fluticasone propionate when using a chlorofluorocarbon (CFC) pMDI compared with a DPI, implying that the device is an important parameter in the clinical evaluation of inhaled products.24 In the current studies, the budesonide/formoterol pMDI resulted in somewhat lower plasma exposure of budesonide compared with the marketed budesonide DPI formulation in adults with asthma (study 1) and in children with asthma (study 2). This lower plasma exposure with the pMDI compared with the budesonide DPI formulation could be due to differences in inhalation technique or differences in inherent pharmaceutical properties of the compared devices. Similar plasma concentrations compared with budesonide pMDI were observed in adults with asthma, an observation that was expected given that the formulations were identical with the exception of formoterol content. It should be noted that the experimental budesonide HFA pMDI was specifically formulated for use in this clinical development program as a comparator with the combination product and is not marketed in any country.

The use of ICSs greatly reduces the risk of systemic AEs compared with orally administered corticosteroids. However, systemic absorption of the corticosteroid has the potential to produce systemic effects, such as hypothalamic pituitary adrenal axis suppression, slowing of growth in children, and osteoporosis in older individuals. Therefore, the somewhat lower budesonide plasma levels after budesonide/formoterol pMDI compared with budesonide DPI in adults and children with asthma are of special interest. The safety profile for budesonide delivered via the DPI has been well established based on numerous clinical trials and extensive clinical experience.8,25 Importantly, long-term daily inhalation of budesonide DPI has no negative effect on final height in children,26 despite reductions in growth velocity observed in short-term studies. In addition, data from pregnancy registries in Sweden demonstrate no increased risk of malformations27,28 or other adverse perinatal outcomes29 in the fetuses of mothers using inhaled budesonide during pregnancy. In addition, maintenance therapy with inhaled budesonide at doses of 200 to 400 µg twice daily in nursing women with asthma has resulted in negligible systemic budesonide exposure in breast-fed infants.30 Based on the present data that systemic exposure to budesonide administered with formoterol using the combination pMDI is lower compared with the currently marketed DPI, daily inhalation of budesonide/formoterol pMDI should not be expected to cause any new concern for corticosteroid-induced systemic side effects.

The similar pharmacokinetic profile of budesonide in patients with asthma and COPD after inhalation of budesonide/formoterol pMDI is not unexpected because the amount of drug reaching the lungs is primarily determined by the extent of filtration/impaction in the oropharynx.31 Thus, even a difference in the geometry of the asthmatic and bronchitic lung, which might be expected, would not change the total lung deposition.31 However, this observation does not exclude a difference in regional deposition between asthmatic and COPD patients or degree of removal of the drug from the lung by mucociliary clearance. Also of note is the age difference between patients in the asthma and COPD groups; the mean age was 36 years for the asthma group and 53 years for the COPD group. Age difference did not affect the amount of drug reaching the lungs and systemic circulation, which were similar between these patient groups; however, a slightly longer t1/2 for budesonide in the COPD group might be attributable to the difference in mean age.

Comparison of budesonide pharmacokinetics after administration of budesonide/formoterol pMDI in adults and children with asthma (studies 1 and 3, respectively) suggests that systemic exposure in children is approximately 30% lower (on a dose-corrected basis) than in adults. This lower exposure in children could be due to differences in the way in which children and adults use the pMDI, resulting in greater oropharyngeal deposition in children compared with adults. Also, smaller upper airway size in children might result in greater impaction of the pMDI aerosol in the oropharyngeal region, resulting in relatively less drug delivery to the lung.32

Previous data reported by Anhøj et al33 obtained using budesonide pMDI, albeit with a different CFC formulation marketed in Europe, suggest that budesonide plasma exposure is similar in children and adults. One possible explanation for the difference in results obtained in the present series of studies and that of Anhøj et al is that, unlike in the current studies, the latter study used a spacer device with the CFC pMDI, which precludes the need for coordination of dose actuation and inhalation. The results of a previous study indicated that the addition of a spacer to the budesonide CFC pMDI substantially improved lung deposition34; however, it is not clear whether similar results would be observed when using a spacer with the budesonide HFA pMDI, as clinical data are not available.

Formoterol
Pharmacokinetic trends for formoterol were similar to those observed with budesonide, although there was only 1 comparator product, formoterol DPI (not marketed in the United States). Inhaled formoterol has been studied extensively in clinical trials9 and generally is considered to be safe and efficacious. Formoterol, a β2-adrenergic agonist, has a predictable AE profile, including headache, tremor, palpitations, and decreased serum potassium.35 These effects can be related to total systemic exposure to formoterol. Formoterol pharmacokinetic data are sparse in the published literature, with only 1 study identified36 that used plasma concentration measurements.

In adults with asthma (study 1), budesonide/formoterol pMDI resulted in slightly lower plasma concentrations of formoterol than formoterol DPI. In children (study 2), systemic exposure to formoterol was determined by formoterol levels in the urine. A similar amount of unchanged formoterol was detected in the urine after treatment with both budesonide/formoterol pMDI and formoterol DPI. Similar to budesonide, systemic exposure to formoterol from budesonide/formoterol pMDI appears to be lower in children (approximately 3.5% of nominal dose excreted unchanged in urine) compared with adults (approximately 8%).

After single-dose administration in patients with COPD (study 3), budesonide/formoterol pMDI resulted in a somewhat higher formoterol exposure compared with formoterol DPI, whereas patients with asthma (study 1) experienced a slightly lower formoterol exposure after budesonide/formoterol pMDI compared with formoterol DPI. These findings were reflected in the direct comparison of formoterol exposure with budesonide/formoterol pMDI in the 2 disease states (study 3), in which patients with COPD experienced slightly higher formoterol exposure compared with patients with asthma. The reason for these differences is not known, but all changes were small and without clinical importance.

In study 1, the relative bioavailability of formoterol from budesonide/formoterol pMDI and formoterol DPI was determined using a sensitive plasma assay and urinary excretion of unchanged drug. Results of both analyses yielded nearly identical values for relative bioavailability, indicating that use of urinary excretion can be a useful alternative to extensive plasma sampling after inhalation of formoterol.

In conclusion, the results of these 3 pharmacokinetic studies indicated that systemic exposure to budesonide and formoterol from the combination pMDI is comparable with or slightly lower than that produced by the individual marketed DPI products (budesonide DPI and formoterol DPI), for which there exists a considerable amount of safety experience from numerous clinical trials and extensive clinical experience. The plasma exposure to budesonide and formoterol administered via the combination pMDI appeared to be generally lower in children than in adults. In addition, the differences noted between patients with asthma or COPD appear to be without clinical relevance. These findings indicate that the systemic safety profile of the budesonide/formoterol pMDI should be at least as good as that of the DPI monoproducts.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors acknowledge Leslie Sell, PhD (formerly from Scientific Connexions [Newtown, Pennsylvania]), and Michael Theisen, PhD, from Scientific Connexions for medical writing support. The authors also thank Ingegerd Johannes-Hellberg and Per Mandahl (AstraZeneca, Lund, Sweden) and Janet Jobes and Rose Fulmer (AstraZeneca LP, Wilmington, Delaware) for their contributions to the conduct of the studies.

DOI: 10.1177/0091270008322122

Financial disclosure: Medical writing support was funded by AstraZeneca LP.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007. NHLBI publication no. 08-4051.

2. Global Initiative for Chronic Obstructive Lung Disease Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2005 Update. Available at: http://www.goldcopd.com/download.asp?intId=234.

3. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22: 912-919.[Abstract/Free Full Text]

4. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic pulmonary disease: a randomised controlled trial. Lancet. 2003;361: 449-456.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 µg)/salmeterol (50 µg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124: 834-843.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166: 1084-1091.[Abstract/Free Full Text]

7. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21: 74-81.[Abstract/Free Full Text]

8. Banov CH. The role of budesonide in adults and children with mild-to-moderate persistent asthma. J Asthma. 2004;41: 5-17.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Berger WE. The use of inhaled formoterol in the treatment of asthma. Ann Allergy Asthma Immunol. 2006;97: 24-33.[Web of Science][Medline] [Order article via Infotrieve]

10. Lalloo UG, Malolepszy J, Kozma D, et al. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to moderate asthma. Chest. 2003;123: 1480-1487.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Tal A, Simon G, Vermeulen JH, et al. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatr Pulmonol. 2002;34: 342-350.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Zetterström O, Buhl R, Mellem H, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. Eur Respir J. 2001;18: 262-268.[Abstract/Free Full Text]

13. Rosenhall L, Elvstrand A, Tilling B, et al. One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort® Turbuhaler®) for the treatment of asthma. Respir Med. 2003;97: 702-708.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Agertoft L, Laulund LW, Harrison LI, Pedersen S. Influence of particle size on lung deposition and pharmacokinetics of beclomethasone dipropionate in children. Pediatr Pulmonol. 2003;35: 192-199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Donnelly R, Seale JP. Clinical pharmacokinetics of inhaled budesonide. Clin Pharmacokinet. 2001;40: 427-440.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

16. Agertoft L, Andersen A, Weibull E, Pedersen S. Systemic availability and pharmacokinetics of nebulised budesonide in preschool children. Arch Dis Child. 1999;80: 241-247.[Abstract/Free Full Text]

17. Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study. Lancet. 2000;356: 556-561.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. McCormack PL, Lyseng-Williamson KA. Budesonide/formoterol: a review of its use as maintenance and reliever inhalation therapy in asthma. Drugs. 2007;67: 2407-2431.[Web of Science][Medline] [Order article via Infotrieve]

19. Derom E, Strandgården K, Schelfhout V, Borgström L, Pauwels R. Lung deposition and efficacy of inhaled formoterol in patients with moderate to severe COPD. Respir Med. 2007;101: 1931-1941.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Noonan M, Rosenwasser L, Martin P, O'Brien CD, O'Dowd L. Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial. Drugs. 2006;66: 2235-2254.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Corren J, Korenblat PE, Miller CJ, O'Brien CD, Mezzanotte WS. Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma. Clin Ther. 2007;29: 823-843.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

22. Miller CJ, Senn S, Mezzanotte WS. Bronchodilation of formoterol administered with budesonide: device and formulation effects. Contemp Clin Trials. 2008;29: 114-124.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

23. Zitt MJ. Properties of the ideal corticosteroid therapy. Allergy Asthma Proc. 2005;26: 173-182.[Web of Science][Medline] [Order article via Infotrieve]

24. Martin RJ, Szefler SJ, Chinchilli VM, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med. 2002;165: 1377-1383.[Abstract/Free Full Text]

25. Brogden RN, McTavish D. Budesonide: an updated review of its pharmacological properties and therapeutic efficacy in asthma and rhinitis. Drugs. 1992;44: 375-407.[Web of Science][Medline] [Order article via Infotrieve]

26. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med. 2000;343: 1064-1069.[Abstract/Free Full Text]

27. Källén B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol. 1999;93: 392-395.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

28. Ericson A, Källén B. Use of drugs during pregnancy: unique Swedish registration method that can be improved. Swedish Medical Products Agency. 1999;1: 8-11.

29. Norjavaara E, Gerhardsson de Verdier M. Normal pregnancy outcomes in a population-based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol. 2003;111: 736-742.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

30. Fält A, Bengtsson T, Kennedy BM, et al. Exposure of infants to budesonide through breast milk of asthmatic mothers. J Allergy Clin Immunol. 2007;120: 798-802.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

31. Borgström L, Olsson B, Thorsson L. Degree of throat deposition can explain the variability in lung deposition of inhaled drugs. J Aerosol Med. 2006;19: 473-483.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

32. Berg E. In vitro properties of pressurized metered dose inhalers with and without spacer devices. J Aerosol Med. 1995;8: S3-S11.

33. Anhøj J, 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]

34. Thorsson L, Kenyon C, Newman SP, Borgström L. Lung deposition of budesonide in asthmatics: a comparison of different formulations. Int J Pharm. 1998;168: 119-127.[CrossRef][Web of Science]

35. Sovani MP, Whale CI, Tattersfield AE. A benefit-risk assessment of inhaled long-acting β2-agonists in the management of obstructive pulmonary disease. Drug Saf. 2004;27: 689-715.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

36. Lecaillon JB, Kaiser G, Palmisano M, Morgan J, Della Cioppa G. Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via aerolizerTM. Eur J Clin Pharmacol. 1999;55: 131-138.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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