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PERBEDAAN ICS INTRACLASS
Muhammad Amin COPD Day 2018
Differences between asthma and chronic obstructive pulmonary disease (COPD) with regard to airway inflammation profile.Belvisi 2004
ICS paling efektif mengontrol asma , lini pertama
Meredam inflamasi Menurunkan hiperresponsif dan mengontrol
simtom Absorbsi ke sistemik, dosis tinggi risiko
pneumonia
Konsentrasi tinggi di SN, sedikit efek sistemik
Fraksi tinggi mencapai SN, sedikit tertelan Ikatan yang tinggi di SN, retensi lama di SN Eliminasi sistemik cepat
Kortikosteroid mengaktivasi dan menekan gen yang relevan
Mekanisme mengalami progres yang yang bermakna
Fig. Glucocorticoid suppression of activated inflammatory genes. Barnes 2010
Stimulus inflamasi
IL-1ß,TNF-α
Mekanisme Kerja Steroid
NF-κB
Glucocorticoid receptor
HDAC2
Kortikosteroid
Histone acetylation
Inflammation
Inflammatory genes e.g. IL-8, MMP-9
Barnes 2010
Lung tissue eosinophils may be cleared by luminalentry rather than by apoptosis Belvisi 2004
These effects of corticosteroids are produced through inhibiting the recruitment of inflammatory cells into the airway by suppressing the production of chemotactic mediators and adhesion molecules and by inhibiting the survival in the airways of inflammatory cells, such as eosinophils, T-lymphocytes and mast cells. Barnes 2010
Figure Chemical structures of inhaled glucocorticoids Barnes 2010
Padden
Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids
Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids, Volume: 98, Issue: 6, Pages: 523-536, First published: 15 May 2006, DOI: (10.1111/j.1742-7843.2006.pto_355.x)
Edsbacker
Perjalanan partikel inhaler
Figure Pharmacokinetics of inhaled glucocorticoids. GI = gastrointestinal Barnes 2010
Fraksi ICS deposit di orofaring ditelan dan diabsorbsi
Dimetabolisir di hepar sebelum masuk ke sistemik (first-pass metabolism FPM)
Budesonide and fluticasone propionate (FP), FPM > beclomethasone dipropionate (BDP) – sistemik lebih rendah
ICS ideal : Bioavailabiliti paru Oral bioavailability Absorbsi sistemik rendah Klirens sistemik tinggi Ikatan dengan protein tinggi
Padden
Padden
Beberapa ICS ada dipasaran Efikasi masing-masing belum banyak studi Sistem penghantaran penting flat dose-response –sulit membedakan
efikasi Sebagian besar membandingkan efek
sistemik
Budesonid vs BDP sebanding dengan dosis yang sama
FP 2 xlebih poten vs budesonid dan BDP Budesonid dan FP efek sistemik < vs BDP,
triamcinolone dan flunisolide Mometasone dan efek sistemik kurang
BUD mengalami esterifikasi asam lemak di paru memengaruhi karakter distribusi dan metabolisme setelah inhalasi
BUD teresterifikasi retensi lama Dosis sekali sehari
The reversible process of budesonide endogenous esterification with fatty acids in the airway/lung tissue, showing the intracellular depot of budesonide and illustrating the variable lipophilicity of budesonide, ie, moderate lipophilicity in the airway epithelial lining fluid and very high lipophilicity intracellularly where a portion of budesonide – not bound to GCS receptor – is reversibly converted to highly lipophilic fatty acid esters.Janson
Prolongs duration of
action
Increases airway
selectivity
Miller-Larsson et al. 1998 and Wieslander et al. 1997
Active Budesonide available to bind to receptor
ICS lama di paru Riversibel Efikasi dan kemanan (retensi lama)
ICS ICS ICS ester ICS paru Ikatan ICS-reseptor ICS
Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids
Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids, Volume: 98, Issue: 6, Pages: 523-536, First published: 15 May 2006, DOI: (10.1111/j.1742-7843.2006.pto_355.x)
Edsbacker
ESTERIFIKASI
Rasio topikal : sistemik tinggi Manfaat klinis dan farmakokinetik diteliti
ekstensif Efektif bila diberikan sekali sehari Retensi (animal) di SN lebih lama dari pada
ekspektasi akibat efek lipofilik saja BUD eliminasi waktu paro plasma pendek
(4,5 jam), memanjang karena budesonide fatty acid esters
Studi kinetic (binatang), mengalami esterifikasi intrasel di SN dengan asam lemak rantai panjang : cepat , ekstensif, riversibel
Setelah inhalasi 80% sebagai ester 20 menit Esterifikasi yang tinggi juga di studi invitro
dengan sel epitel bronkus manusia FP tidak mengalami esterifikasi tak bisa
dikonsumsi sekali sehari. Esterifikasi bisa terjadi pada ciclesonide
Konsentrasi BUD di jaringan paru > 9 x vs di plasma , setelah 1 dan 6 jam inhalasi (diperoleh simultan)
Retensi FP deposisi di jaringan paru terutama di SN sentral pada pasien dengan banyak mukus dan faal paru jelek
Esterifikasi intrasel spesifik BUD tidak FP Konjugasi asam lemak BUD membentuk
depo intrasel, selanjutnya BUD dilepas dalam periode ekstensi melalui aktivitas lipase
Keberadaan BUDester di jaringan paru sampai 43 jam
Konsentrasi BUD cukup tinggi untuk 50%s aturasi dengan glukokortikoid reseptor, cukup untuk aktivitas > 10 jam
Kadar FP plasma 2x setelah terapi 1 minggu vs dosis tunggal, tidak jelas apakah karena retensi di SN
BUD akumulasi lebih sedikit, yang membedakan farmakokinetik
Relevansi klinik efek esterifikasi pada durasi kerja BUD setelah inhalasi
lipofilisiti, menyebabkan sedikit larut dan diabsorbsi di SN, dan ikatan dengan GR
Sebagian besar tidak larut di sapu bulu getar Tidak terjadi pada partikel BUD di lumen SN FP di intrasel epitel pelapis lumen > BUDester BUDester cepat larut
Paru : FP waktu paroh > lama vs BUD FP waktu paro plasma > BUD setelah inhalasi
BUD terdeteksi di SN sentral dan perifer 10
jam setelah inhalasi BUD oleat Tidak terdeteksi setelah 29 jam BUD palmitat hanya dideteksi di SN sentral FP terdeteksi di SN sentral dan perifer dalam
22 jam
Brink
Rerata dari konsentrasi plasma, eliminasi waktu paro BUD : FP = 3: 14
FP dapat sampai 24 jam Variasi interindividu FP > BUD
Mekanisme ICS difference References
In Vitro In Vitro
Physicochemical properties
Lipophilicity Higher for FLU 28
Aqueous solubility Higher for FLU BUD
27
Dissolution rate in lung lining fluid Higher for FLU BUD
27,28 33,34
Airway pharmacokinetics
Airway epithelial absorption Higher for FLU BUD
29-32
Rate of airway absorption Faster for BUD 33,34
Intracellular esterification In airway/lung tissue
Only for BUD 37,38
Immunosuppressive effects
Suppression of pro - inflammatory Higher for FLU 39-41
Cytokines and leukocyte adhesion
molecules
Mekanisme ICS difference References
In Vitro In Vitro
Effects on local immunity
Protection of airway epithelial barrier Higher for BUD 55
Expression of immune defense genes in airway epithelial cells
Higher for BUD 56
Prevention of adhesion and / or internalization of bacteria to airway epithelial cells
Higher for BUD 55
Prevention of bacteria-induced reducation of bacteria recognition receptors in COPD macrophages
Higher for BUD 57
Phagocytosis of bacteria by COPD macrophages
Increased for BUD 61
Proprietary and Confidential ©AstraZeneca 2013 • FOR INTERNAL USE ONLY
Nannini LJ, et. al. Cochrane Database Syst Rev 2008; Issue 3 CD003794.
ICS/LABA type Hazard or Rate Ratio
(95% CI)
Exacerbations (mod/severe)
Flu/Salm vs. placebo 0.74 (0.69, 0.80) **
26% rate reduction
Bud/Form vs. placebo 0.74 (0.62, 0.88) **
26% rate reduction
Overall Mortality
Flu/Salm vs. placebo 0.79 (0.65, 0.97) **
21% risk reduction
Bud/Form vs. placebo 0.78 (0.35, 1.73) [ns]
22% risk reduction
** statistically significant decrease p<0.01 [ns] = no statistically significant
COPD exacerbation prevention in RCTs comparing different ICS/LABA with placebo
ICS/LABA vs.
placebo
Annualised exacerbation rate
in placebo group
% reduction vs. placebo
(saving in events/patient-
yr)
TRISTAN FLU/SAL 500/50 μg bid 1.30 25 (0.33)
Szafranski et al BUD/FORM 320/9 μg bid 1.80 24 (0.43)
Calverley et al BUD/FORM 320/9 μg bid 1.80 24 (0.43)
ICS/LABA + tiotropium
Vs.Tiotropium + placebo
Annualised exacerbation rate
in tiotropium group
% reduction with
ICS/LABA vs. placebo
(saving in events/patient-
yr)
Aaron et al 2
Canadian Triple Study
FLU/SAL 500/50 μg bid
1.61 15 (0.24) ns
CLIMB 3 AZ Triple study
BUD/FORM 320/9 μg bid
1.41 * 62 (0.87) #
Monotherapy RCTs vs. placebo 1
Triple-regimen RCTs adding ICS/LABA to LAMA
1. Calverley et al. Proc Am Thorac Soc 2004; 1: 121–124.
2. Aaron et al. Ann Intern Med 2007; 146: 545–555. 3. Welte et al. Am J Repir Crit Care Med 2009; 180: 741–750.
ns = not significant. Not a very high differential drop out occurred in this study * rate extrapolated from a 3-mo. study (CLIMB [antibiotic use alone was excluded from severe exacerbation definition]) # Note differential drop out was not a feature of the CLIMB study but has been reported in all other studies listed
Proprietary and Confidential ©AstraZeneca 2013 • FOR INTERNAL USE ONLY
Nannini LJ, et. al. Cochrane Database Syst Rev 2012; 9: CD006829.
Study/ subgroup
Combination
n/N
LABA
n/N Odds ratio
M-H, Random, 95% CI
FLU/SAL
Mahler 2002 2/165 0/160 4.91 (0.23, 103.04)
SCO100470 2/518 4/532 0.51 (0.09, 2.81)
Hanania 2003 0/178 1/177 0.33 (0.01, 8.15)
TRISTAN 7/358 9/372 0.80 (0.30, 2.18)
O’Donnell 2006 0/62 0/59 Not estimable
Kardos 2007 23/507 7/487 3.26 (1.39, 7.67)
TORCH 303/1546 205/1542 1.59 (1.31, 1.93)
Ferguson 2008 29/394 15/388 1.98 (1.04, 3.75)
Anzueto 2009 26/394 10/403 2.78 (1.32, 5.84)
Subtotal (95% CI) 4122 4120 1.75 (1.25, 2.45)
Total events: 392 (Combination), 251 (LABA)
Heterogeneity: Tau2 = 0.06; Chi2 = 10.03, df = 7 (P=0.19); I2 =30%
Test for overall effect: Z = 3.23 (P = 0.001)
BUD/FORM
Calverley 2003 8/254 7/255 1.15 (0.41, 3.23)
Tashkin 2008 10/558 5/284 1.02 (0.34, 3.01)
Rennard 2009 37/988 17/495 1.09 (0.61, 1.96)
Subtotal (95% CI) 1800 1034 1.09 (0.69, 1.73)
Total events: 55 (Combination), 29 (LABA)
Heterogeneity: Tau2 = 0.00; Chi2 = 0.03, df = 2 (P=0.99); I2 = 0%
Test for overall effect: Z = 0.37 (P = 0.71)
Total (95% CI) 5922 5154 1.55 [ 1.20, 2.01 ]
Total events: 447 (Combination), 280 (LABA)
Heterogeneity: Tau2 = 0.04; Chi2 = 12.84, df = 10 (P=0.23); I2 = 22%
Test for overall effect: Z = 3.32 (P = 0.0009)
Test for subgroup differences: Chi2 = 2.62, df = 1 (P=0.11), I2 = 62%
Analysis broken down by ICS/LABA type
0.01 0.1 1 10 100
Favours combination
Favours LABA
Pneumonia Risk in COPD Patients (Stratified by ICS Type)
Meta-analysis of ICS use for <3 years duration
Singh S et al Curr Opin Pulm Med 2010; 16: 118.
Corticosteroid type
(No. of studies)
ICS containing
regimen
n/N (%)
Non ICS
control
n/N (%)
Adjusted Pneumonia
Odd Ratio
(95% CI)
Fluticasone (16)* 612 / 7,919
(7.7)
364 / 7,705
(4.7)
1.67 (1.47, 1.89) **
Budesonide ( 7)* 140 / 3,801
(3.7)
94 / 2,760
(3.4)
1.19 (0.92, 1.53) [ns]
Mometasone (1) 25 / 616
(4.1)
6 / 295
(2.0)
2.00 (0.83, 4.81) [ns]
* data inclusive of combinations with exposure lasting up to 3 years with fluticasone and budesonide ** statistically significant increase with fluticasone p<0.0001 [ns] = no statistically significant increase in risk detected
• Up to 3 years exposure with fluticasone was associated with a significant 67% increase in risk. • No increase in pneumonia was detected with budesonide with up to 3 yrs exposure • 1 of the 24 trials focused on mometasone for <1 year, i.e. long-term risk with this ICS is unclear
Increasing COPD severity increases risk of infection
Bacterial colonisation of airway
lumen increases
Increased exacerbation and pneumonia risk (1,2)
FP vs.
BUD
FP has a 100 X slower dissolution rate and is slow to penetrate in to tissue (3)
FP is therefore retained at higher local concentrations
in mucus (4)
FP 10-fold > potency than BUD for Immune suppression effect on innate immunity (macrophages) (5)
COPD
disease
factors
Increased strain on
host defences in
airway
1. Jenkins et al Respiratory Research 2009,10: 59. 2. Crim et al Eur Respir J 2009, 34: 641 3. Högger and Rohdewald, Rev Contemp Pharm 1998 4. Dalby C et al. Respir Res 2009; 10:104 5. Ek A et al. Allergy 1999. 54; 691
Ruge CA et al The Lancet / Respiratory Medicine (published online June 4th 2013)
What happens to a drug after deposition in the lungs?
1. Contact with airway surface liquid 2. Absorption of active ingredients across pulmonary epithelium, controlled mainly by physiochemical properties
(dissolution rate and lipophilicity) 3. Clearance of non-dissolved particles by mucocilliary clearance or phagocytosis
API Properties • Molecular Weight • Charge • Solubility • Lipophilicity
Formulation Properties • Disintegration • Dissolution • Particle Size • Wettability
Aerosol particle Peripheral lung Central Lung
Mucociliary clearance
Macrophage clearance
Systemic Circulation
Alveolar
macrophage
Surfactant
Alveolar
epithelium
Endothelium
Blood
Endothelium
Blood
Bronchial
epithelium
Surfactant
Mucus
1. Wedzicha JA et al. AJRCCM 2008
2. Calverley et al. Chest 2011;139:505
3. Patterson C et al Respiratory Research 2012,13:40
4. Ek A et al Allergy (1999). 54: 691
5. Miller-Larsson et al. AJRCCM (2000). 162: 145
6. Johnsson M et al Allergy (1995) 50:s11-14
7. Dalby C, et al. Respir Res (2009); 10:104
8. Larsson K et al. Journal of Internal Medicine, 2013; doi:10.1111/joim.12067
9. Janson C et al. BMJ 2013; 346:f3306 doi: 10.1136/bmj.f3306
Mucosa/Lung tissue
Local bacteria proliferation during infections, e.g. virus
Exacerbation (Tracheobronchitis)
Pneumonia (Tissue infection)
Bacteria Fluticasone Fluticasone/GCS-receptor
ASL : Airway Surface liquid Bud/For: Budesonide/Formoterol Flu/Sal: Fluticasone/Salmeterol
Budesonide
Budesonide/GCS-receptor Protracted
exacerbations
Bacterial colonization of the lower airways with a
spectrum of pathogens observed in COPD patients
ASL
Bud/For Flu/Sal
Water solubility (μg/mL)
Dissolution time (human BAL fluid in vitro)
Flunisolide 140 <2 min
Triamcinolone acetonide
21 n.d.
Budesonide 16 6 min
Beclomethasone 17-propionate
16 n.d.
Fluticasone 17-propionate
0.16 >8h
Beclomethasone dipropionate
0.13 >5h
Högger and Rohdewald, Rev Contemp Pharm 1998;9: 501-522
n.d.= no data
Proprietary and Confidential ©AstraZeneca 2013 • FOR INTERNAL USE ONLY Halpin DMG, et. al. Int J Clin Pract, July 2011, 65(7): 764–774.
Results of the Indirect Comparisons
Using the Butcher Method*
Outcome Odds Ratio 95% Confidence Interval
Pneumonia adverse
events
0.47 0.28-0.80
Pneumonia serious
adverse events
0.41 0.19-0.86
Pneumonia-related
mortality
0.18 0.01-4.10
*Odds ratios < 1 favour budesonide/ formoterol versus
fluticasone/salmeterol
Proprietary and Confidential ©AstraZeneca 2013 • FOR INTERNAL USE ONLY
In Canada, 5255 COPD patients were treated with an ICS/LABA before matching
• 3969 (76%) patients in this cohort used FLU/SAL
• Only 36% had exacerbations pre-index
• More bud/form vs. flu/sal pats. had a first ICS/LABA initiated by a specialist (8% more; was this a potential confounder?)
• Antibiotics were not evaluated as a definition of exacerbations
• Patients were tracked for only 1 year
Healthcare utilisation in the first year after initiating ICS/LABA therapy
Blais L, et. al. Clin Ther 2010; 32 (7): 1320.
Courses of oral steroids/year 0.66 0.79 0.85 (0.72, 1.00)
ED visits/year 0.16 0.23 0.75 (0.58, 0.97)
Hospital admissions/year 0.11 0.21 0.61 (0.47, 0.81)
Addition of a tiotropium prescription/year
1.63 2.01 0.71 (0.57, 0.89)
A retrospective observational cohort study
BUD oleat dibentuk cepat in vivo di SN setelah inhalasi dan masih dapat dideteksi 2 hari setelah inhalasi tunggal
Esterifikasi BUD terjadi intrasel dalam paru, dan kerja berkelanjutan (sustained) karena konjugasi asam lemak
Keberadaan FP di jaringan paru sampai 22 jam setelah inhalasi akibat tidak larut di lumen SN , tidak dapat akses ke ke reseptor glukokortikoid intra sel
TERIMA KASIH
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