4. Pharmacokinetics: Systemic
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540c
• Systemic absorption (GI, lung)
• If water soluble ↑lung uptake
(rapid onset) e.g. budesonide
• Binding to albumin/transcortin
• First-pass metabolism at liver
• CYP 450 dependent mixed function
oxidases: to inactive
• Glucuronyl transferase: conjugate to
water soluble
• Inactivate & Urinary excretion at
kidney
• 11B-HSD type 2 (11B-dehydrogenase)
1st pass metabolism: Budesonide, FP > BDP
5. Pharmacokinetics: Local
• Esterification (↑lipophilicity)
• Retention in tissue e.g. Budesonide, triamcinolone, ciclesonide, BMP
• Longer duration of action
• Hydrolysis by esterase
• Activate drug and release
• Others
• Beclomethasone dipropionate (BDP)
to beclomethasone 17α-monopropionate (BMP); higher affinity for GR
Middleton 8th edition
Miller-Larsson A. et al. Drug Metab Dispos. 1998;26(7):623-630
6. GR Binding Characteristics
• GR = Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1
• Affinity, duration, and SE
• Regulator: Degree of occupancy of the binding cleft
https://en.wikipedia.org/wiki/Glucocorticoid_receptor#/media/File:Glucocorticoid_receptor.png
7. SElective Glucocorticosteroid Receptor
Agonists (SEGRA)
• Classic GR activities: GR agonist
• ↓SE from the steroid backbone
• Tissue retention, longevity of
action: ongoing developed
Middleton 8th edition
10. Properties of Drugs: Receptor Binding, Tissue
Deposition, Vd
• Lipophilic property α lung retention, GR binding affinity, duration of
action
• FF >> MF ≥ FP > TAA >> BUD ≥ des-CIC > FLU ≥ BMP
• Soluble intracellular esters (esterification): Budesonide, triamcinolone,
ciclesonide, BMP
• Lipophilicity α Vd, plasma T1/2
• But ↓SE from fluticasone
• Almost complete 1st pass metabolism in the liver
• PC of GCs: vary greatly (up to tenfold)
• After oral intake of the same dose to normal volunteers
Middleton 8th edition
Clark TJH. Effect of beclomethasone dipropionate delivered
by aerosol in patients with asthma. Lancet 1972; 1: 1361–4.
11. ICS vs oral GCs
• ↓4X effect on HPA axis ICS
(same degree of antiasthma efficacy)
FF = longest lung retention, highest potency
- OD dose
Therapeutic Index Values
• <1 for mid/high doses of BDP, BUD and TAA
• 1 for FLU
• >1 for CIC, FP, MF and FF
Peter T. Daley-Yates, corticosteroids potency
and therapeutic index, BJCP 2015
12. Modern ICS
• High receptor affinity, retained in AW ↑efficacy
• Rapidly metabolized after absorption from the GI tract ↓SE
Middleton 8th edition
17. Effects on Cells
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540
18. Mechanism of Actions
• Hours to days
• Cytoplasmic GR-α
• Gene switch on & off, mRNA degrade,
co-activator binding
Genomic
• Seconds to minutes
• mGR, cGR, direct interaction
• Vascular permeability, AW perfusion,
remodeling
Non-
genomic
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
19. Interaction with Beta-2 Adrenoceptor
Peter J. Barnes: Inhaled Corticosteroids; Pharmaceuticals 2010, 3, 514-540
25. Stepwise approach – pharmacotherapy
(children ≤5 years)
GINA 2018, Box 6-5 (3/8)
Infrequent
viral wheezing
and no or
few interval
symptoms
Symptom pattern consistent with asthma
and asthma symptoms not well-controlled, or
≥3 exacerbations per year
Symptom pattern not consistent with asthma but
wheezing episodes occur frequently, e.g. every
6–8 weeks.
Give diagnostic trial for 3 months.
Asthma diagnosis, and
not well-controlled on
low dose ICS
Not well-
controlled
on double
ICS
First check diagnosis, inhaler skills,
adherence, exposures
CONSIDER
THIS STEP FOR
CHILDREN WITH:
RELIEVER
Other
controller
options
PREFERRED
CONTROLLER
CHOICE
As-needed short-acting beta2-agonist (all children)
Leukotriene receptor antagonist (LTRA)
Intermittent ICS
Low dose ICS + LTRA Add LTRA
Inc. ICS
frequency
Add intermitt ICS
Daily low dose ICS
Double
‘low dose’
ICS
Continue
controller
& refer for
specialist
assessment
STEP 1 STEP 2
STEP 3
STEP 4
29. The Inhaled Steroid Treatment
As Regular Therapy in Early Asthma (START Study)
• Population
: Recent onset (< 2 yr)
Mild asthma
Aged 5-66 years
• N = 7241 (5155 completed 3 year-study)
• Duration
: 3 + 2 = 5 years
• Visit: q 3 mo (+/-14 days)
• Primary outcome
• Db blind phase: time to 1st SARE
• All 5 years: post BD FEV1 change
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.
30. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 3 Years
Helen K Reddel et al., Should recommendations about starting inhaled corticosteroid treatment for mild asthma
be based on symptom frequency: a post-hoc efficacy analysis of the START study, Lancet 2017; 389: 157–66
31. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 5 Years
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.
PostBD
PreBD
OR = 0.61; (P <.001)
32. The Inhaled Steroid Treatment As Regular Therapy
in Early Asthma (START Study) X 5 Years
William W. et al, The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up:
Effectiveness of early intervention with budesonide in mild persistent asthma; J Allergy Clin Immunol 2008;121:1167-74.
33. Implications from START Trial
• Low dose ICS in recent onset mild
asthma
• ↑Time to 1st SARE (severe asthma-
related event)
• ↓Risk of SARE
• ↓Systemic GCs, additional med use
• ↑pre & postBD FEV1 change from
baseline
• ↑Symptom free days
• Low dose ICS in
+ve risk of AE
GINA
2018
34. The Symbicort Given as Needed
in Mild Asthma (SYGMA) 1 trial
• Population
: Aged 12 years or older
mild asthma at GINA step 2
• N = 3849
• Duration
: 52 weeks
• Primary outcome
• Weeks with well controlled
(Hypothesis: Symbicort was superior to SABA)
35. OR = 1.14 (P = 0.046)
14% higher in the budesonide–formoterol group than in the terbutaline group.
OR = 0.64; (95% CI = 0.57 to 0.73)
36% higher in the budesonide maintenance group than in the budesonide –
formoterol group.
57 vs 340 mcg (17% of that in the budesonide maintenance group)
SE: terbutaline>budesonide maintenance> budesonide–formoterol) but not notably
SE led to stop: terbutaline>budesonide maintenance> budesonide–formoterol
36. The Symbicort Given as Needed
in Mild Asthma (SYGMA) 2 trial
• Population
: Aged 12 years or older
mild asthma at GINA step 2
• N = 4215
• Duration
: 52 weeks
• Primary outcome
: Annualized rate of severe
asthma exacerbations
(Hypothesis: Symbicort was non-inferior to
Budesonide maintenance)
• No electronic reminder (real life)
37. Median daily dose of ICS: Bud/for was 75% lower than Bud maintenance
Same median No. of days with systemic GCs
38. Implications from SYGMA Trial: Personalized
Goal (Symptom control or ↓AE)
Adherence
Preference (SE concern, regular/prn)
Asthma
Socioeconomic,
Concern,
Behavior
Comorbid
Symptom
Risk of AE
QoL
Lung function
45. Pregnancy
• Budesonide (Pulmicort®) is recommended as ICS of choice during
pregnancy
• large amount of reassuring human gestational safety data
• Others (such as beclomethasone [Qvar®], fluticasone [Flovent®],
flunisolide [Aerobid®], mometasome [Asmanex®], and triamcinolone
[Azmacort®]
• Not been proven to be unsafe during pregnancy
• Can be continued in patients well-controlled prior to pregnancy
https://acaai.org/asthma/who-has-asthma/pregnancy
46. Lactation
• Amount of medicine in the breast milk = low
• e.g. BDP, BUD, FP, combination FP/salmeterol
• Some asthma medicines (e.g. formoterol, omalizumab, montelukast)
• Not known whether or not the active ingredient is excreted into breast milk
• Feeding the baby just before each daily dose and avoiding feeding
until 4 hours after the dose
http://www.asthmahandbook.org.au/populations/pregnant-women/breastfeeding
47. Link for The US National Library of Medicine’s
Drugs and Lactation Database (LactMed)
https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
49. Local
• HPA axis suppression
• Adrenal insufficiency
• Growth velocity suppression
• ↓BMD
• Immunity disturb
• Diabetes
• Skin thinning
• Cataract
• Glaucoma
• Pharyngitis
• Dysphonia
• Reflex cough
• Bronchospasm
• Oropharyngeal candidiasis
• Xerostomia
• Halitosis, caries, gingivitis, taste
perception change
Systemic
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
Prevention: Rinse after use
50. Adrenal Insufficiency
• Dose and duration dependent
• Rare in low to medium dose of ICS in short period of time
• Concomitant use of other GCs route
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
51. Recommend: FP ≥ 400 mcg/d (high dose)
in preadolescent: test HPA axis quarterly
52. the Canadian asthma guidelines
S&S of AI (High index of suspicious)
≥ 6 months ICS in
• High dose
• Medium dose + Risk factors1
Risk factors1
• Higher end of the range
• Prolonged duration
• Concomitant use of nasal and topical GCs
• Recent/frequent short courses oral steroids
• High level of adherence
• Smaller body mass for age
Issa-El-Khoury K et al., CSACI position statement: systemic effect of inhaled corticosteroids on adrenal
suppression in the management of pediatric asthma. Allergy, Asthma Clin Immunol. 2015;11:9.
the Canadian Society of Allergy and Clinical Immunology
:CSACI Position Statement: AI Screening
53. • By asthma itself
• Growth velocity & final adult height*
• Variable results in studies
• Unknown if permanent or temporary slowing growth velocity
• Should monitor periodically
• A Cochrane review1
• Intermittent vs daily ICSs in 532 asthma patients
• Modest suppression in growth (0.41 cm) in daily compared with intermittent
treatment
Growth Delay
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
1Chauhan BF, Chartrand C, Ducharme FM. Intermittent versus daily inhaled corticosteroids for
persistent asthma in children and adults. Cochrane Database Syst Rev 2013;(2):CD009611.
55. Kelly HW et al., CAMP Research Group. Effect of inhaled glucocorticoids
in childhood on adult height. N Engl J Med. 2012;367:904–12
The decrease was not progressive or cumulative
The CAMP Study
56. Bone Mineral Density
• By asthma itself
• Variable results in meta-analysis, studies
• Trend toward ↓BMD and ↑fracture risk for long-term mod- to high-dose ICS
• Caution if risk for osteoporosis and fractures
Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced osteoporosis:
an update on effects and management. J Allergy Clin Immunol. 2013;132:1019–30.
57. Effect on Immunity
• ↑Pneumonia in adult COPD
• Nested case control study from Korea
• ↑risk of TB in long-term high dose ICS users
• Disseminated varicella infection, HZV in systemic GCs
• A retrospective cohort
• Chicken pox outbreaks was associated with oral GCs use
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
58. Diabetes
• Variable results
• Trend toward ↑progression of diabetes in adult
• Paucity of study in children
• Should monitor in diabetic patient
• A large cohort Canadian study: Adult patients with COPD treated with
ICS (esp. high dose)
• ↑Risk of development and progression of diabetes
• A cross-sectional study: non diabetic children with asthma
• ↑Mean HbA1c (5.44 ± 0.75 %) among non-diabetic children with asthma
compared to the healthy control (5.14 ± 0.41 %)
• Not correlate with the cumulative dose or time of usage
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
59. Ocular Complication
• Subcapsular, nuclear cataract
• Greater in older > children
• The CAMP study: 1 child after 6 years ICS use suspected PSC
• No evidence of ↑glaucoma risk
• Monitor IOP esp. in elderly on prolonged ICS use
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
60. Skin Complication (from case report)
• Skin thinning, bruising/purpura (more common in adults)
• Reported in patients on high dose ICS
• Acne
• Hypertrichosis (onset 1 month – 3 years)
• Hair depigmentation
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
61. Psychiatric Morbidity
• A study conducted in the Netherlands
• Alterations in behavior in the pediatric population
• The CAMP study:
• Greater improvement in the total score on the Children’s Depression
Inventory in the budesonide vs placebo (a decline of 3.2 vs. 2.2, P = 0.01)
• A cross-sectional study
• High dose ICS is negatively associated with mental well being
Hossny E et al, The use of inhaled corticosteroids in pediatric asthma: update, World Allergy Organ J 2016 Aug 12;9:26.
Ref139: Age 4-9 YO on MF-DPI 100, 200 mcg vs placebo 52 weeks then follow 3 month
Ref240: FF/VI 200/25, 100/25 no AI (= placebo) vs oral pred 10mg/d on last 7 days of the end(positive ctr:)