1

Update on Prostaglandin Analogues Used for

the Treatment of Glaucoma

2

Learning Objectives

Review the structure and mechanism of action of the commonly used prostaglandin analogues for treatment of glaucoma

Review the efficacy of the commonly used prostaglandin analogues Know the side effects commonly associated with prostaglandins

3

Introduction

Prostaglandin analogues are currently used as a first-line treatment for glaucoma because they effectively lower IOP

Each prostaglandin analogue has a unique receptor-binding profile, but most agents have similar efficacy

Compared with other antiglaucoma medications, prostaglandin analogues: – Reduce IOP to a greater extent

– Provide good control over IOP fluctuations

– Produce few systemic adverse events

Prostaglandin analogues have similar side effects– Cause different degrees of hyperaemia, iris pigmentation changes, and

eyelash growth

IOP = intraocular pressureMarquis RE et al. Drugs Aging. 2005;22(1):1–21; Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Takagi Y et al. Exp Eye Res. 2004;78:767–776; van der Valk R et al. Ophthalmology. 2005;112:1177–1185; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52.

4

Prostaglandin Analogues: Structure

PGF2α = prostaglandin F2α

Adapted with permission from Takagi Y et al. Exp Eye Res. 2004;78:767–776 and Marquis RE et al. Management of glaucoma: focus on pharmacological therapy. Drugs Aging. 2005;22(1):1–21.

5

Prostaglandin Analogues:Mechanism of Action

FP = prostaglandin FAdapted with permission from Weinreb RN et al. Prostaglandin effects on the uveoscleral outflow pathway. In: Krieglsten GK, ed. Glaucoma Update VI; Springer-Verlag, Berlin. 2000:197–202.

6

SAFLUTAN™† (tafluprost) Has High FP Receptor Affinity: 12 Times Greater Than Latanoprost

Prostaglandin Receptor-Binding Affinity (Moles per Liter)a

Prostaglandin Analogueb FP EP1 EP2 EP3 IP/DP TP

PGF2α 1.2 × 10−8 3.2 × 10−7 6.4 × 10−6 1.6 × 10−7 >10−4 > 10−4

Latanoprost acid 1.0 × 10−8 5.0 × 10−6 >10−4 2.8 × 10−5 >10−4 > 10−4

Travoprost 3.5 × 10−9 3.0 × 10−8 >10−4 2.4 × 10−5 >10−4 > 10−4

Bimatoprost 4.5 × 10−9 6.5 × 10−7 >10−4 >10−4 >10−4 3.4 × 10−5

Tafluprost 0.5 × 10−9 >10−6 >10−6 6.7 × 10−8 >10−6 > 10−6

EC50 = half maximal effective concentration; FP = prostaglandin F; PGF2α = prostaglandin F2α aReceptor binding assessed according to EC50 values.bData refer to active drug product.Stjernschantz JW. From PGF2α-isopropyl ester to latanoprost: a review of the development of Xalantan. Inv Ophthalmol Vis Sci. 2001;42(6):1134–1145; Stjernschantz JW et al. Mechanism and clinical significance of prostaglandin induced iris pigmentation. Surv Ophthalmol. 2002;47(suppl 1):S162–S175; Takagi Y et al. Exp Eye Res. 2004;78:767–776.†SAFLUTAN is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Higher FP affinity has not been correlated with an increase in either efficacy or safety

7

Substantial IOP-Lowering Efficacy of Prostaglandin Analogues is Consistent Across Products

IOP = intraocular pressureParrish RK et al. Am J Ophthalmol. 2003;135(5):688–703.

0

5

10

15

20

25

30

35

40

08:00 12:00 16:00 20:00

Latanoprost

Bimatoprost

Travoprost

Time

IOP

Red

uct

ion

(%

)

8

Prostaglandin Analogues ShowComparable Efficacy

IOP Reduction

IOP = intraocular pressureParrish RK et al. Am J Ophthalmol. 2003;135:688–703; Netland PA et al. Am J Ophthalmol. 2001;132:472–484; Gandolfi S et al. Adv Ther. 2001;18(3):110–121; Noecker RS et al. Am J Ophthalmol. 2003;135:55–63.

Multi-center, randomized, investigator-masked studies

of patients with ocular hypertension or primary open-angle glaucoma. Study drugs given once daily.

-12

-6

0

Latanoprost 0.005%

Bimatoprost 0.03%

Travoprost 0.004%

ParrishN = 410

12 weeks

NetlandN = 390

12 months

GandolfiN = 232

3 months

NoeckerN = 269

6 months

p < 0.001

Me

an

IO

P R

ed

uc

tio

n (

mm

Hg

) a

t 8

:00

Ac

ros

s P

ub

lis

he

d C

om

pa

rati

ve

Tri

als

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IOP-Lowering Efficacy: Prostaglandin Analogues vs Other Antiglaucoma Treatments

TreatmentMean Change From Baseline as % Change in IOP

Peak Trough

Bimatoprost 33 28

Travoprost 31 29

Latanoprost 31 28

Timolol 27 26

Brimonidine 25 18

Betaxolol 23 20

Dorzolamide 22 17

Brinzolamide 17 17

IOP = intraocular pressureAdapted with permission from van der Valk R et al. Ophthalmology. 2005;112:1177–1185.

10

Adverse Events Associated WithProstaglandin Analogues

Prostaglandin analogues have a better systemic safety profile than other antiglaucoma therapies

Common side effects of prostaglandin analogues:– Conjunctival hyperaemia

– Iris pigmentation changes

– Eyelash growth

Marquis RE et al. Drugs Aging. 2005;22(1):1–21; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52.

11

Conjunctival Hyperaemia With Prostaglandin Analogues

Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Stewart WC et al. Am J Ophthalmol. 2003;135:314–320.

0

10

20

30

40

50

60

70

80

Latanoprost Bimatoprost Travoprost

Pat

ien

ts (

%)

12

Conjunctival Hyperaemia With Prostaglandin Analogues (cont)

Xalatan Summary of Product Characteristics. Pharmacia Ltd., Kent, UK.: 2007; Travatan Summary of Product Characteristics. Alcon Laboratories (UK) Ltd., Hemel Hempstead, UK.: 2006; Lumigan Summary of Product Characteristics. Allergan Ltd., Marlow, Bucks, UK.: 2007.

0

10

20

30

40

50

Xalatan®

(latanoprost)Travatan®

(travoprost)Lumigan®

(bimatoprost)

Pat

ien

ts (

%)

13

Conclusions

The IOP-lowering effect of prostaglandin analogues is primarily mediated by the FP receptor

Prostaglandin analogues have similar and substantial IOP lowering effects

Compared with other antiglaucoma medications, prostaglandin analogues: – Reduce IOP to a greater extent

– Produce fewer systemic adverse events

Ocular side effects are common to all prostaglandin analogues– Conjunctival hyperaemia, which occurs with varying frequencies among

these medications

– Iris pigmentation changes

– Eyelash growth

FP = prostaglandin F; IOP = intraocular pressureTakagi Y et al. Exp Eye Res. 2004;78:767–776; Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; van der Valk R et al. Ophthalmology. 2005;112:1177–1185; Marquis RE et al. Drugs Aging. 2005;22(1):1–21; Holló G. Expert Opin Drug Saf. 2007;6(1):45–52.