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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

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


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)


Heterogeneity: Tau2 = 0.00; Chi2 = 0.03, df = 2 (P=0.99); I2 = 0%


Total (95% CI) 5922 5154 1.55 [ 1.20, 2.01 ]


Heterogeneity: Tau2 = 0.04; Chi2 = 12.84, df = 10 (P=0.23); I2 = 22%


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


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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