Medikamentöse Behandlung des Makulaödems1. NSAID2. Steroide3. Karboanhydrase-Hemmer4. Anti-VEGF

Pharmakotherapie des MakulaödemsWirkungsorte

Innere BRS

• NSAIDs• Steroide

Äussere BRS

• NSAIDs• Steroide

• Karbo-anhydraseInhibitoren

Ionen- und FlüssigkeitstransportBlut-Retina-Schranke

o o o o o o o o o o o o o o o

2 K

3 Na

K/Na 2 Cl Na 2 HCO

HCO 3

Cl Na

K Cl

K

Na

H

3

6 mV

HCO

Na

CAI NSAIDsANPCFTR

Kortison

Pharmakologie des zystoiden Makulaödems

Arachidonsäure

5 HPETE

LTA4

LTB4 LTC4

Membranlipide

PGG2

PGE2PGI2

TXA2

TXB2

PGD2

PGF2α

PermeabilitätTc Aggregation Chemotaxis

CyclooxygenaseCOX-1 and COX-2

H2O

Phospholipase A2

NSAIDs

Permeabilität

Medikamentöse Behandlung des Makulaödems

Nicht-steroidale Antiinflammatorika

NSAID: Voltaren Ophta®Acular®Ocuflur®etc.

Akutes CMÖ (21-90 Tage post-op)

Studie Therapie Dauer Visus CMÖ im FA

Heier 2001 Ketoralac 3/12 ↑ ↓

Prednisolon 3/12 ↑ ↓

Ketoralac & 3/12 ↑ ↑ ↓ ↓Prednisolon

Behandlung von CMÖ nach KataraktextraktionNSAIDs vs. 1% Prednisolon

• Topisch: Prednisolon

• Subtenon/retrobulbär: Methylprednisolon

Triamcinolone, 40 mg (1 ml)

• Intravitreal: Triamcinolone, 2-4 mg pars plana

• Implantat: Fluocinolon, Dexamethason

• Systemisch: p.o. oder i.v. 40 - 100 mg/d

Medikamentöse Behandlung des Makulaödems

Table 59-2 Goodman & Gilman 9th Edition*approximated from the literature

Relative Potenz der Kortikosteroide

Corticosteroid Relative Potencies

Cortisone 0.8

Cortisol 1

Prednisone 4

Methylprednisolone 5

Triamcinolone 5Fluorination at 9αposition increases corticosteroid receptor binding

Betamethasone 25

Dexamethasone 25

Fluocinolone acetonide 25*

Triamcinolon

TriamcinolonOhne Konservierungsmittel

Corticosteroid Equivalents Over Time

20

15

10

5

1

1000

750

250

0

500

Time (mo)

Cor

ticos

tero

id E

quiv

alen

ce

1 Hr Day 2Day 1

20

15

10

5

1

00 1 2 3 4

Dexamethasone (700 µg)Triamcinolone acetonide (4-mg injection)Fluocinolone

Intravitreal injection dexamethasone (700 µg)

TA free drug levels over time estimated from the dissolution kinetics of the Kenalog® depot in Kim H et al. Retina. 2006;26:523-530. Dexamethasone: Data on file. Irvine, CA: Allergan, Inc.Fluocinolone acetonide: Driot JY et al. J Ocul Pharm Ther. 2004;20:269-275; Beer PM et al. Ophthalmology. 2003;110:681-686.Triamcinolone acetonide: Inoue M et al. Am J Ophthalmol. 2004;138:1046-1048.

Irvine-Gass-Syndrom – post Kat.-OPWas würden Sie tun?

Steroide: Subtenon

• Triamcinolon• 40 mg subtenon• Wiederholung bis zu 3 x

1 Monat Abstand• Tropfanästhesie30 G Nadel

Cave: IOD Erhöhung in 36%

1 Tag nach Injektion

Befund nach intravitrealer Injektion

1 Monat nach Injektion

Steroid Drug-delivery Implants

Medidur Retisert Vitrasert

•Approximate duration of action: 2.5 years

Retisert prescribing information. http://www.bausch.com/en_US/downloads/ecp/pharma/general/retisert_pkginsert.pdf.

Retisert: Fluocinolon

•Approximate duration of action: At least 2 years

Kane FE, et al. Expert Opin Drug Delivery 2008;5:1039-1046.

Iluvien: Fluocinolon

Insertion via 25G intravitrealinjector

Iluvien: Fluocinolon

in vitro Average Daily Wet Release Rates

0.5

0.4

0.3

0.2

0.23 ug/day0.45 ug/day

0.1

0.00 3 6 9 12 15 18 21 24 27 30

Alimera Sciences. Data on file

Time (months)

Fluo

cino

lone

Rel

ease

d (µ

g/da

y)Iluvien

Steroid ImplantatDexamethasone

Zugelassen:•Venenverschlüsse•Uveitis

Steroid ImplantatDexamethason

Dexamethason Konzentration im Glaskörper

1. Weitjens O et al. Ophthalmology 2002; 109: 1887–91.2. Weitjens O et al. Am J Ophthalmol 1998; 125: 673–9. 3. Weitjens O et al. Am J Ophthalmol 1997; 123: 358–63.4. Weitjens O et al. Am J Ophthalmol 1999; 128: 192–7. 5. Gan IM et al. Graefes Arch Clin Exp Ophthalmol 2005; 243: 1186–9.

Art der Anwendung Dosis (mg)Verhältnis im Glaskörper

(Dosis [mg]: Cmax im Glaskörper [ng/ml])

Topisch1 0,3 3,7

Oral2 7,5 1,44

Peribulbär3 5,0 2,6

Subkonjunktival4 2,5 29

Intravitreal5 0,4 980

Medikamentöse Behandlung des Makulaödemes

Karboanhydrase-Hemmer:

Oral: Diamox®

Tropfen: Trusopt®, Azopt®

Karboanhydrasehemmer

o o o o o

2 K

3 Na

K/Na 2 ClNa 2 HCO

HCO3

Cl Na

K Cl

K

Na

H

36 mV

HCO

Na

IIIIIIIII

IIIIIIIIIIIII

IIIIIIIIIIIII

IIIIIIIII

Gao et al. Nature Medicine 2007;13:181-188

Extracellular carbonic anhydrase mediates retinal vascular permeability

Karboanhydrasehemmer und Makulaödem

• Leckage beim RPE

RP, Uveitis

• 500 mg Anfangsdosis / Tag

• Langzeit DosisreduktionTitrierung durch den Patienten

• Tachyphylaxie

1980s

Laser photocoagulation

2000

Photodynamic therapy

2005 2006 2007

Pegaptanib Ranibizumab

Bevacizumab off-label

Aflibercept

2011 2012

Pharmacological characteristics ofanti-VEGF therapies

1. Novartis Europharm Ltd. Lucentis SmPC. September 20112. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf3. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 20114. Genentech, Inc. Avastin® prescribing information. September 2011

Ranibizumab Aflibercept Bevacizumab

Company Genentech/Novartis Regeneron/Bayer Genentech/Roche

MOA / class Anti-VEGF-A antibody fragment [targets all VEGF-A isoforms]1

Anti-VEGF-A/PIGF/VEGF-B recombinant fusion protein [targets all VEGF-A isoforms,

VEGF-B and PIGF]3Anti-VEGF-A full-length

antibody [targets all VEGF-A isoforms]4

Molecular weight 48 kDa2 97–115 kDa3 149 kDa4

Structure

2

3

VEGFR1 VEGFR2

Ranibizumab Aflibercept

Company Genentech/Novartis Regeneron/Bayer

MOA / class Anti-VEGF-A antibody fragment [targets all VEGF-A isoforms]1

Anti-VEGF-A/PIGF/VEGF-B recombinant fusion protein [targets all VEGF-A isoforms,

VEGF-B and PIGF]4

Molecular weight 48 kDa2 97–115 kDa4

Half-life in the rabbit eye 2.88 days3 4–6 days

Systemic elimination half-life ~2 hours2 4–5 days5,6

Licensed indications

Wet AMD, visual impairment due to DME, visual impairment due to ME secondary to RVO (BRVO and CRVO)1

Wet AMD in the US4

1. Novartis Europharm Ltd. Lucentis SmPC. September 2011; 2. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf; 3. Bakri SJ et al. Ophthalmology 2007;114:2179–82; 4. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 2011; 5. Dixon JA et al. Expert Opin Investig Drugs 2009;18:1573–80; 6. Tew et al. Clin Cancer Res 2010;16:358–66; 7. Genentech, Inc. Avastin® prescribing information. September 2011

Pharmacological characteristics ofanti-VEGF therapies

Intravitreal aflibercept approved by the FDA for neovascular AMD under the trade name EYLEA®, recently also approved in Australia but it is not yet approved elsewhere

VIEW Studies: Mean Change inVisual Acuity Baseline to Week 96

LOCF; Full analysis set; VIEW 1: OCTs mandatory at baseline, weeks 4, 12, 24, 36, and all visits weeks 52-96;VIEW 2: OCTs mandatory at all visits

VIEW Studies: Mean Change inCentral Retinal Thickness to Week 96

+8.5+6.8

+8.0

+5.9

99.2%CI: (-4.7, 1.3)