Update on
Prostaglandin Analogues Used for
the Treatment of Glaucoma
1
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
2
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 pressure
Marquis 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.
3
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.
4
Prostaglandin Analogues:
Mechanism of Action
FP = prostaglandin F
Adapted 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.
5
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
 Higher FP affinity has not been correlated with an increase in either efficacy or safety
EC50 = half maximal effective concentration; FP = prostaglandin F; PGF2α = prostaglandin F2α
aReceptor binding assessed according to EC
50 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 prostaglandininduced 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.
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Substantial IOP-Lowering Efficacy of Prostaglandin
Analogues is Consistent Across Products
40
Latanoprost
Bimatoprost
Travoprost
IOP Reduction (%)
35
30
25
20
15
10
5
0
08:00
12:00
16:00
20:00
Time
IOP = intraocular pressure
Parrish RK et al. Am J Ophthalmol. 2003;135(5):688–703.
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Prostaglandin Analogues Show
Comparable Efficacy
IOP Reduction
Mean IOP Reduction (mmHg) at 8:00
Across Published Comparative Trials
0
Parrish
N = 410
12 weeks
Netland
N = 390
12 months
Gandolfi
N = 232
3 months
Noecker
N = 269
6 months
Multi-center, randomized,
investigator-masked studies
of patients with ocular
hypertension or primary
open-angle glaucoma.
Study drugs given once
daily.
-6
p < 0.001
Latanoprost 0.005%
Bimatoprost 0.03%
-12
Travoprost 0.004%
IOP = intraocular pressure
Parrish 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.
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IOP-Lowering Efficacy: Prostaglandin Analogues
vs Other Antiglaucoma Treatments
Mean Change From Baseline as % Change in IOP
Treatment
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 pressure
Adapted with permission from van der Valk R et al. Ophthalmology. 2005;112:1177–1185.
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Adverse Events Associated With
Prostaglandin 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.
10
Conjunctival Hyperaemia
With Prostaglandin Analogues
80
70
Patients (%)
60
50
40
30
20
10
0
Latanoprost
Bimatoprost
Travoprost
Parrish RK et al. Am J Ophthalmol. 2003;135:688–703; Stewart WC et al. Am J Ophthalmol. 2003;135:314–320.
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Conjunctival Hyperaemia
With Prostaglandin Analogues (cont)
50
Patients (%)
40
30
20
10
0
Xalatan®
(latanoprost)
Travatan®
(travoprost)
Lumigan®
(bimatoprost)
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.
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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 pressure
Takagi 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.
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