Pharmacologic Importance of the Reversible Fatty Acid Conjugation of  Budesonide Studied in a Rat Cell Line <i>In Vitro</i>

Aims The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 mg, 800 mg or 1600 mg administered twice daily by a dry-powder inhaler (TurbuhalerA) in adult patients with mild asthma. Methods A total of 38 patients received budesonide by inhalation, 13 received 400 mg twice daily, 12 received 800 mg twice daily and 13 received 1600 mg twice daily. Mean FEV 1 at inclusion was 3.4, 4.0 and 3.9 l min −1 in the three groups,respectively. Blood samples were taken after a single dose, and after 3 weeks of daily treatment, for pharmacokinetic evaluation. Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry.Results Eleven evaluable patients remained in each dose group. Mean time to peak budesonide plasma concentration (t max ) was short (0.28-0.40 h) and did not differ between treatment groups. Budesonide concentrations declined rapidly thereafter, indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. C max was 1.4(2.0) nmol l −1 (single (repeated) doses), 2.6(3.6) nmol l −1 and 5.4(6.4) nmol l −1 after 400, 800 and 1600 mg twice daily, respectively. The corresponding results for the area under the plasma concentration vs time curve (AUC) were 271(325), 490(628) and 915(1096) nmol l −1 min. Ninety percent confidence intervals for pairwise dose-normalized C max and AUC comparisons between groups were large but contained unity in all cases, thus indicating dose-proportional pharmacokinetics. Regression on analysis supported these findings. Mean AUC after repeated doses (AUC(0,12 h,RD)) was on average 23% higher than the mean AUC after single doses (AUC(0,2,SD)( P=0.04) with no significant differences between doses, indicating slight accumulation following bid dosing. Conclusions In this relatively small study, budesonide inhaled via TurbuhalerA appeared to have dose-proportional pharmacokinetics, both within and above the clinically recommended dose range for asthmatic patients.Keywords: budesonide, pharmacokinetics, TurbuhalerA orally. This is because the inhaled drug acts locally, so a Introduction lower dose can be employed, which reduces systemic exposure and results in fewer side effects [1]. As a Over the last four decades, glucocorticosteroids (GCS) have been the most effective therapy available for the consequence of the improved safety profile, inhaled steroids are now commonly used across a wide spectrum maintenance treatment of asthma. Unfortunately, oral administration of GCS is often associated with a high of asthma severity. Budesonide was developed to further enhance topical incidence of systemic side effects. Inhaled GCS have a better ratio of local to systemic effects than those given anti-inflammatory effects while minimizing the systemic effects observed with other GCS. Both preclinical and clinical studies with inhaled budesonide have demon- activity and systemic GCS effect over a wide range of

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“…anti-inflammatory action [25,26]. The overall extent of is not yet known, but could possibly contribute to the…”

Section: Pharmacokinetic Evaluation Resultsmentioning

confidence: 99%

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler^®

Kaiser

Aaronson

Dockhorn³

et al. 1999

Brit J Clinical Pharma

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“…Budesonide can be conjugated with fatty acids to form an ester that subsequently is hydrolyzed to release free budesonide (11,12); this reservoir effect occurs in adult lung tissue and likely improves the duration of local glucocorticoid action.…”

Section: Clinical Relevancementioning

confidence: 99%

Antiinflammatory Effects of Budesonide in Human Fetal Lung

Barrette¹,

Roberts

Chapin³

et al. 2016

Am J Respir Cell Mol Biol

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Lung inflammation in premature infants contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease with long-term sequelae. Pilot studies administering budesonide suspended in surfactant have found reduced BPD without the apparent adverse effects that occur with systemic dexamethasone therapy. Our objective was to determine budesonide potency, stability, and antiinflammatory effects in human fetal lung. We cultured explants of second-trimester fetal lung with budesonide or dexamethasone and used microscopy, immunoassays, RNA sequencing, liquid chromatography/tandem mass spectrometry, and pulsating bubble surfactometry. Budesonide suppressed secreted chemokines IL-8 and CCL2 (MCP-1) within 4 hours, reaching a 90% decrease at 12 hours, which was fully reversed 72 hours after removal of the steroid. Half-maximal effects occurred at 0.04-0.05 nM, representing a fivefold greater potency than for dexamethasone. Budesonide significantly induced 3.6% and repressed 2.8% of 14,500 sequenced mRNAs by 1.6-to 95-fold, including 119 genes that contribute to the glucocorticoid inflammatory transcriptome; some are known targets of nuclear factor-kB. By global proteomics, 22 secreted inflammatory proteins were hormonally regulated. Two glucocorticoid-regulated genes of interest because of their association with lung disease are CHI3L1 and IL1RL1. Budesonide retained activity in the presence of surfactant and did not alter its surface properties. There was some formation of palmitate-budesonide in lung tissue but no detectable metabolism to inactive 16a-hydroxy prednisolone. We concluded that budesonide is a potent and stable antiinflammatory glucocorticoid in human fetal lung in vitro, supporting a beneficial antiinflammatory response to lung-targeted budesonide:surfactant treatment of infants for the prevention of BPD.

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“…Blood samples were taken at 0, 0. 17 5,110,112,113,114,116,118, and 120 hours after the first dose. Serum was separated from cellular material by sedimentation and subsequent centrifugation and then stored at -20°C until analyzed.…”

Section: Investigational Proceduresmentioning

confidence: 99%

Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects

Wagner

Krishnaswami

Dimova

et al. 2001

The Journal of Clinical Pharma

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Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

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Pharmacologic Importance of the Reversible Fatty Acid Conjugation of Budesonide Studied in a Rat Cell Line In Vitro

Cited by 43 publications

References 18 publications

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler^®

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler^®

Antiinflammatory Effects of Budesonide in Human Fetal Lung

Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects

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Pharmacologic Importance of the Reversible Fatty Acid Conjugation of Budesonide Studied in a Rat Cell Line In Vitro

Cited by 43 publications

References 18 publications

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler®

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler®

Antiinflammatory Effects of Budesonide in Human Fetal Lung

Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects

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Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler^®

Dose‐proportional pharmacokinetics of budesonide inhaled via Turbuhaler^®