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`

`

`562
`
`Surv Ophthalmol 41 (Suppl 2) February 1997
`
`CAMRAS, ALM
`
`TABLE 1
`
`Efi‘icacy and Side Eflects ofProstaglandins or their Prodmgs/Analogues in Initial Randomized,
`Double-masked, Vehicle-controlled Clinical Trials
`Lowest
`NT
`SD or
`Ctrl
`PG or
`PG
`or
`Freq ><
`IOP
`Initial
`IOP
`Max
`
`Analogue
`OHT
`n
`Concentration
`Duration
`(mm Hg)
`’I‘IOP
`(mm Hg)
`¢IOP
`
`PGFZa-TS
`
`PGE2 Analogue
`(RS 18492)
`
`PGD2
`BW245C
`
`PGFm—IE
`
`NT
`NT
`
`NT
`
`NT
`NT
`
`NT
`
`OHT
`OHT
`OHT
`
`NT
`
`NT
`
`18
`15
`
`20
`
`5—8
`7
`
`6
`
`30
`10
`11—13
`
`12
`
`6
`
`0.5 %
`0.125—0.5%
`
`0.02%
`
`0.01—0.1%
`0.005%
`
`SD
`SD
`
`SD
`
`SD
`SD
`
`0.0004%—0.04%
`
`0.002%
`0.002%
`0.001%—0.002%
`
`SD or
`BIDX 16d
`BIDX 1d
`B1D><7d
`BIDX 8d
`
`0.005%—0.025%
`
`SD
`
`0.1%—0.4%
`
`14
`16
`
`15
`
`l4
`11
`
`15
`
`30
`25
`24.5
`
`14
`
`12.5
`
`—
`—
`
`+
`
`+
`+
`
`—
`
`—
`—
`—
`
`—
`
`—
`
`10
`12.5
`
`13
`
`12
`10
`
`9.5
`
`24
`17
`18
`
`12
`
`10
`
`30%
`20%
`
`10%
`
`15%
`10%
`
`35%
`
`20%
`30%
`25%
`
`15%
`
`20%
`
`IS—Propionate-
`PGFZu-IE
`S-1033
`
`Unoprostone
`
`PhXA34
`
`Latanoprost
`
`NT
`
`NT
`NT
`OHT
`NT
`
`NT
`
`OHT
`OHT
`
`NT
`
`OHT
`
`OHT
`OHT
`OHT
`
`7—10
`
`8—11
`7-8
`29—34
`16—18
`
`0.12%
`
`0.03%—0.12%
`0.06%—0.12%
`0.03%-0.12%
`0.003%—0.03%
`
`8—10
`
`0.003%—0-.03%
`
`8
`9—10
`
`6—16
`
`15
`
`6—9
`11—12
`20
`
`0.001%—0.03%
`0.003%—0.01%
`
`0.003%—0.01%
`
`0.003%—0.01%
`
`0.006%
`0.002%—0.01%
`0.006%
`
`SD or
`BIDXSd
`
`SD or
`BID><4wks
`SD
`BID><2wks
`BIDX4wks
`SD or
`QDX7d
`SD or
`BIDXSd
`SD
`BIDX lwk
`
`SD or
`BIDXSd
`BID><4wks
`
`QDXSd
`SD
`QD><2wks or
`BIDXZwks
`
`12
`
`15
`14.5
`22.5
`12.5
`
`12
`
`23
`25
`
`15
`
`22.5
`
`23
`23
`23
`
`—
`
`—
`—
`—
`—
`
`—
`
`—
`—
`
`—
`
`—
`
`e
`—
`-—
`
`10
`
`11.5
`10.5
`19.5
`8
`
`8.5
`
`14.5
`15
`
`10
`
`14
`
`17
`17
`15
`
`15%
`
`25%
`25%
`15%
`35%
`
`30%
`
`35%
`40%
`
`35%
`
`35%
`
`25%
`25%
`35%
`
`Abbreviations: PG = prostaglandin; NT = normotensive volunteers; OHT = ocular hypertensive and/0r glaucoma patients; n =
`number of subjects evaluated for each dose; SD = single dose; Freq = frequency; Ctrl = control of contralateral vehicle-treated,
`parallel group of vehicle-treated, or baseline measurements; IOP = intraocular pressure; 4‘ = increase; Max = maximum; ~ll =
`decrease; CH 2 conjunctiva] hyperemia; PGFZa-TS = prostaglandin Flu tromethamine salt; HAS = headaches; FBS = foreign body
`sensation; PGFZa-IE = prostaglandin Fh-isopropyl ester; Rx = treatment.
`
`treated with the 125 or 250 pg doses), and occa-
`sional erythema of the skin of the lower lid. Pupil-
`lary diameter was not altered. Neither aqueous flare
`nor an anterior cellular response was observed in
`any eyes.27
`
`PGE2 Analogue
`After demonstrating an ocular hypotensive effect
`in rabbits,48 a single application of PGE2 analogue,
`RS 18492 (Fig. 1) 0.02%, was administered to one
`
`eye in each of 20 normotensive volunteers in a ran-
`domized, double-masked fashion.19 This PG ana-
`
`logue caused an initial mean rise in IOP of as much
`as 3—4 mm Hg, peaking at 1—2 hours. As an extreme,
`two individual patients showed rises of 13—20 mm
`Hg. Following this initial hypertensive response,
`mean IOP was reduced by no more than 1—2 mm
`Hg at six hours. Similar to the effects seen with the
`PGF2u-TS, this PGE2 analogue caused conjunctiva]
`hyperemia, aching, tenderness, and photophobia,
`
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`

`INITIAL CLINICAL STUDIES
`
`S63
`
`
`(Continued)
`
`TABLE 1
`
`Time (hrs) Duration Max Maximum
`
`Max ~14IOP
`(hrs)
`CH*
`Irritation* Other Side Effects/Comments
`References
`7—10
`24
`3+
`3+
`HAs, FBS
`Giuffre20
`2—9
`24
`3+
`3+
`HAs, FBS, lid erythema
`Lee et al27
`
`HAs, FBS, tenderness, photophobia
`
`Flach & Eliasonl9
`
`Itching, FBS, burning
`
`Itching, FBS. burning
`
`Nakajima et al3|
`
`Nakajima et al3'
`
`Dose-dependent CH & irritation; FBS,
`photophobia & pain with higher doses only
`CH usually resolved after 3—4 hrs; mild FBS X 1 hr; Villumsen et al45
`not progressive with multiple dosing
`Max CH occurred 30 min after each dose; mild
`dose-dependent irritation, FBS, discomfort
`
`Camras et a1”
`
`Villumsen & Alm42
`
`Mild dose—dependent PBS
`
`Villumsen & Alm43
`
`Slight & transient smarting sensation; 0.4% produced Ando et al"
`apparent contralateral J/IOP
`
`6
`
`2—4
`
`3
`
`4—1 2
`
`12
`12
`4+6
`
`4—12
`
`2—8
`
`3+6
`
`2
`9
`?
`
`10
`
`12
`
`12
`12
`5—8
`
`?
`
`24
`
`4
`
`4
`
`12—24
`
`12
`12
`12
`
`12
`
`8
`
`10
`
`2—5
`"
`‘.’
`
`48—144
`(2—6d)
`48
`
`24
`48
`48
`
`12
`
`3+
`
`3+
`
`3+
`
`2+
`
`1—2+
`1—2+
`1+2+
`
`1—2+
`
`1+
`
`0
`
`0
`0
`0
`
`2—3+
`
`1+
`
`1—2+
`1—2+
`1+
`
`1+
`
`3+
`
`2+
`
`2+
`
`1—2+
`
`1+
`1+
`1+
`
`1+
`
`1+
`
`0
`
`0
`0
`0
`
`1+
`
`0
`
`1+
`0
`0
`
`1+
`
`1 mmHg ~l/IOP occurred after 2 wks of Rx, but no
`signif. JIIOP was present after 4 wks of Rx
`
`JICH over the 1 wk of Rx; ¢discomfort to 0
`after a few doses
`\l/CH over the 5d of Rx
`
`\l’CH when tonometry was suspended
`No signif CH with repeated doses of 0.006%
`
`¢CH over the 4 wks of Rx; mild irritation was
`signif on day 2 only
`Mild CH reported on single occasion in 2 patients
`
`Sakurai et 8135
`
`Takase et al‘“
`Takase et 211“"
`Azuma et a17
`
`Alm & Villumsen4
`
`Hotehama & Mishima24
`
`Villumsen & Alm44
`Camras et all6
`Hotehama & Mishima24
`
`Alm et al5
`
`Racz et al32
`0
`1+
`24
`15—24
`Hotehama et a125
`0
`0.5—1+
`24
`8
`Nagasubramanian ct al3O
`Max CH on day 2
`0
`1+
`20
`8—20
`
`
`*Graded in relative units of 0—3+ with 0 = absent, 0.5 = barely detectable, 1 = mild, 2 2 moderate, 3 = severe.
`
`beginning within the first hour and lasting up to six
`hours after administration.
`
`PGD2 and its Selective Analogue
`
`Studies have demonstrated that PGD2 and
`BW245C, an agonist selective for the DP—receptor,
`are not only effective ocular hypotensive agents, but
`the best tolerated PCs in terms of the blood—aque—
`ous barrier and ocular surface pathology in rab—
`bits.22’5°~51 Therefore, a dose response study was car-
`
`ried out in 5—9 normotensive volunteers.31 Like the
`
`PGE2 analogue, PGD2 caused a dose-dependent ini-
`tial rise in IOP of 1—4 mm Hg for the 5 ug (0.01%),
`10 ug (0.02%), and 50 ug (0.1%) doses, peaking at
`30 minutes.31 A subsequent mean reduction in IOP
`of no more than 1.5—2 mm Hg peaked at 1.5—2 hours
`after a single application. BW245C 2.5 ug (0.005%)
`induced an initial rise in IOP of 3—4 mm Hg at 30
`minutes, followed by a reduction of 1+1.5 mm Hg at
`three hours (Table 1). PGD2 and BW245C caused
`
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`

`$64
`
`Surv Ophthalmol 41 (Suppl 2) February 1997
`
`CAMRAS, ALM
`
`OH
`-
`
`6H
`
`5"
`
`2.
`
`9H
`?
`
`5”
`
`PGFZa
`
`,.e~\=/\/\coo NH3C(CH20H)3
`
`5H
`
`PGF2(x Tromethamine
`
`0
`
`3_
`
`COOCH3
`“>=c=f\/
`H
`H
`/
`
`CH3
`
`6“
`
`RS-18492
`
`OH
`E
`-
`
`'
`
`4.
`
`.-‘\=/\/\coon
`
`/
`
`é
`
`PGDe
`
`O )
`
`HN
`
`k’m‘VWcoocm
`5. er0
`5H :
`
`.fWCOOH M (
`2
`1' QANV
`6
`5H
`5
`
`9"
`? s‘WCOOCH CH
`
`.
`
`/
`
`a)2
`
`OH
`PGFZa—IE
`
`7
`
`.
`
`3,
`
`9H
`=
`
`0“
`
`..~“\=/\/\COOCH(CH3)2
`
`c‘acocuzcu3
`
`15-Propionate PGFga—IE
`
`9H
`?
`
`5
`
`_
`
`coon
`
`/
`
`S4033
`
`OH
`E W
`'
`3“ _
`
`COOCH(CH3)2
`
`9-
`
`OH
`
`UF-021
`Unoprostone
`
`
`
`BW2450
`
`PhXA34
`
`
`
`PhXA41
`Latanoprost
`
`Fig. 1. Chemical structure ofprostaglandins and their prodrugs/analogues used in clinical trials.
`
`IPR Page 4/8
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`

`

`INITIAL CLINICAL STUDIES
`
`865
`
`conjunctival hyperemia, foreign body sensation, itch-
`ing, and burning during the first two hours after
`application. Neither aqueous flare nor an anterior
`chamber cellular response was observed. Similar to
`the PGE2 analogue and PGFQa tromethamine salt,
`PGD2 and BW—245C had a poor therapeutic index
`and side-effect profile. These findings with BW-245C
`in clinical trials were consistent with a study which
`demonstrated poor tolerance in monkeys.46
`
`PGqu- 1 -Isopropyl Ester (PGFh-IE)
`The first important improvement in therapeutic
`index for PGs occurred with the development of the
`isopropyl ester of PGqu (Fig. 1). The enhanced
`lipophilicity resulting from esterification of the car-
`boxylic acid group improved corneal penetration to
`increase potency.9 Maintaining efficacy similar to that
`of PGFZQ at considerably lower concentrations in rab-
`bits, cats}10 and monkeys, ”‘47 PGFh-IE produced less
`external ocular side effects. Analogous t0 the rela—
`tionship between dipivefrin and epinephrine, PGFh—
`IE is a prodrug of PGFh and is converted to the free
`acid by esterases in the cornea.9
`In a dose-response study in six normotensive vol-
`unteers, single applications of PGFga—IE produced a
`dose—dependent reduction of IOP at 8—12 hours by
`1.9, 1.9, 3.3, and 5.7 mm Hg at doses of 0.1 ug
`(0.0004%), 0.5 pg (0.002%), 2.5 ug (0.01%), and 10
`pg (0.04%), respectively.” Only the highest doses
`showed a tendency toward an initial rise in IOP at
`30 minutes. The reduction of IOP was maintained for
`
`12—24 hours with the higher two doses. Twice-daily
`application of 0.5 ug (0.002%) in 10 normotensive
`volunteers produced a 1.5—2.5 mm Hg reduction of
`IOP for the 16 days of treatment. Compared to PGFga,
`PGan-IF. reduced IOP with a lower incidence and
`intensity of conjunctiva] hyperemia, pain, foreign
`body sensation, and photophobia.42
`Based on these initial favorable results in normo—
`
`tensive volunteers, PGFZa-IE was tested in patients
`with ocular hypertension or glaucoma.”45 Doses of
`0.25 ug (0.001%) or 0.5 ug (0.002%) reduced IOP
`by as much as 6 mm Hg (25%). A 4—6 mm Hg IOP
`reduction was maintained on the eighth day of twice-
`daily treatment.”45 Although conjunctival hyperemia
`and irritation were noted by many patients, these
`side effects were reduced compared to those ob-
`served with PGFm.
`This esterified prodrug of PGFZQ provided evi—
`dence that with appropriate modification of PCs or
`their analogues, external ocular side effects could
`be reduced without sacrificing ocular hypotensive
`efficacy. Nevertheless, local side effects, although
`reduced, persisted at levels sufficient to lead to prob-
`lems with medical compliance, and would prevent
`
`PGF2u-IE from becoming a useful primary therapy
`for glaucoma.
`
`lS-Propionate-PGan-IE
`In an effort to reduce the irritation and conjunc-
`tival hyperemia produced by PGFh-IE, an esterifi-
`cation at the 15-carbon position, in addition to es-
`terification at the carboxylic acid moiety (Fig. 1) was
`tried.43 In a double-masked, dose-response, com-
`parative study with PGqu-IE, 15-propionate-PGF2H-
`IE effectively reduced IOP in 12 normotensive vol-
`unteers, but failed to offer any advantages compared
`to PGFZa-IE in terms of therapeutic index.43
`
`15-Deoxy-PGF2a (8-1033)
`
`5-1033 is PGF2u without the hydroxyl group at the
`15th carbon position (Fig. 1). It was found to reduce
`IOP in rabbits, cats, dogs, and monkeys with mini-
`mal side effects.21 In the only clinical trial using this
`agent, a dose-dependent reduction of IOP of as
`much as 2—3 mm Hg peaked at 2—8 hours after a
`single application of 0.3% solution in six normoten-
`sive volunteers.6 The highest dose of 0.4% resulted
`in both an ipsilateral and contralateral reduction of
`IOP of 4—5 mm Hg at eight hours. This contralat-
`eral effect was difficult to explain. 8-1033 0.3% pro-
`duced mild conjunctiva] hyperemia in three of the
`six subjects, and a slight “smarting” sensation in all
`six patients lasting for a few minutes after a single
`application. Twice-daily application ofS-1033 0.3%
`in the six normotensive volunteers reduced IOP by
`2—3 mm Hg for the eight days of treatment.
`
`Isopropyl Unoprostone, a Modified
`PGF2m Metabolite
`Isopropyl unoprostone (UF—021; Rescula®; 20-
`ethyl—13,14—dihydro-15-keto-PGF2a-isopropyl ester)
`is the isopropyl ester prodrug form of the 20—ethyl
`derivative of the common pulmonary metabolite of
`PGF,‘I (Fig. 1). In a dose-response study involving
`8—11 normotensive volunteers,
`isopropyl
`unoprostone 0.03%, 0.06%, 0.09%, and 0.12%
`caused a dose-dependent reduction of IOP with a
`peak of 1—4 mm Hg at 1—2 hours after a single dose.41
`Compared to all previously discussed PG analogues,
`isopropyl unoprostone seems to be best tolerated
`in terms of external ocular surface side effects.41
`
`In another dose-response study involving normal
`volunteers treated twice daily for two weeks, isopro—
`pyl unoprostone 0.06% or 0.12% produced a simi-
`lar dose-dependent reduction of IOP without ocu-
`lar or systemic side effects.40 In 10 normotensive
`volunteers, isopropyl unoprostone 0.12% caused a
`peak reduction ofIOP of 1—2 mm Hg at six hours?’5
`Twice—daily treatment in seven normotensive volun-
`
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`

`866
`
`Surv Ophthalmol 41 (Suppl 2) February 1997
`
`CAMRAS, ALM
`
`teers reduced IOP for two weeks, but no significant
`IOP reduction was present after four weeks of treat-
`ment.35 In a larger study involving 129 patients with
`elevated IOP, isopropyl unoprostone 0.03%, 0.06%,
`or 0.12%, or placebo was randomly applied twice
`daily for four weeks in these four parallel groups.7 A
`dose—dependent reduction of IOP of 1—3 mm Hg
`(5—15%) was produced with only mild side effects.7
`These initial studies led to evaluation of isopropyl
`unoprostone in larger multicenter studiesf'2 and to
`governmental approval for its use in glaucoma
`therapy in Japan.
`
`PhXA34
`
`PhXA34 (13, l4-dihydro- 15(R,S)- l 7-phenyl-18, 19,
`20—trinor-PGF2u-IE) is a l7—phenyl substituted ana-
`logue of the isopropyl ester of PGF2u (Fig. 1). In ad-
`dition to the phenyl group at the 17th position on
`the carbon chain, the double bond at the €13-14
`is
`reduced. 17-phenyl substituted PGFQG analogues
`were found to be 90 times more potent than PGFzm
`in an in vitro assay which measures leuteolytic activ-
`ity, and considerably more potent in several in vivo
`assays.28 These analogues are selective for the FP—
`receptor, which is the prostanoid receptor respon-
`sible for the reduction of IOP in primates.“39 Al-
`though not an effective ocular hypotensive agent in
`rabbits or cats, PhXA34 produced fewer and less
`severe external ocular side effects than other ana—
`
`logues.i”3v3‘*'38 In monkeys, this PG analogue main—
`tained ocular hypotensive efficacygfia'38
`On the basis of an improved therapeutic index
`found in experimental animals, PhXA34 was evalu-
`ated in clinical trials. In a dose-response study in 16
`normotensive volunteers, PhXA34 1 ug (0.003%), 3
`ug (0.01%), and 10 ug (0.03%) caused a dose-de-
`pendent reduction of IOP by as much as 5 mm Hg,
`peaking at 8—10 hours after a single dose.4 The hy-
`potensive effect lasted for at least 24 hours after each
`application of the higher dose, and was maintained
`during the seven days of treatment. External ocular
`side effects were markedly reduced with this ana-
`logue compared to others.”4 In patients with ocular
`hypertension or glaucoma, PhXA34 0.003% or
`0.01% reduced IOP by as much as 40% on the sec-
`ond day of therapyflfi“H with maintenance of a 20—
`.35% IOP reduction for one week.16 Adverse sensory
`side effects of burning, stinging, irritation, and for-
`eign body sensation after PhXA34 were not signifi-
`cantly different from that noted after vehicle treat-
`ment. Conjunctival hyperemia was significantly
`reduced to a level tolerated by all patients.”44
`
`Latanoprost
`
`PhXA34 is an epimeric mixture. Since the 158-
`
`epimer has only 10% the activity of the 15R—epimer,37
`the R—epimer of PhXA34 is approximately twice as
`potent as the epimeric mixture. This R—epimer, or
`latanoprost (PhXA4l; Xalatan®; Fig. 1), reduced IOP
`by 25—35% in initial clinical trials which evaluated
`dose-response relationships in normotensive volun-
`teers and in patients with ocular hypertension or
`glaucoma.5‘24v‘-’5-3°’$2 Multiple dosing once daily main-
`tained a consistent IOP reduction over at least a 24-
`
`hour period.24253032 Conjunctival hyperemia was
`minimal and adverse symptomatology was not sig-
`nificant. These favorable initial clinical trials led to
`
`testing in international, multicenter trials.1"-"3"3'15"‘9
`Other studies, discussed elsewhere in this supple-
`ment,1*"23"26‘"-"3’49a evaluate its dose-response proper—
`ties, its side effect of iris color darkening (not ob-
`served in the initial small, short—term clinical
`
`trials), and its efficacy in normotension glaucoma,
`in combination with other glaucoma medications,
`and in nocturnal versus diurnal hours.
`
`Conclusions
`
`Since the initial clinical study using the PGFh
`tromethamine salt in 1985, tremendous progress has
`been made in the development ofeffective and well-
`tolerated PG analogues for chronic glaucoma
`therapy. PGFh tromethamine salt is effective, but
`not well tolerated. The PGF.2 analogue (RS 18492),
`PGD,, and BW245C are neither effective nor well
`tolerated, and, in fact, cause an initial rise in IOP.
`PGFEa—IE, lB—propionate—PGFQu-IE, and 8—1033 rep-
`resent improvements in tolerability compared to the
`PGan tromethamine salt with maintenance of ad-
`equate efficacy, but are still likely to produce suffi-
`cient conjunctival hyperemia and/or irritation, pre-
`venting widespread acceptance in chronic glaucoma
`therapyw“ Although no randomized, masked, com-
`parative clinical trials have been carried out with PG
`analogues, isopropyl unoprostone appears to pro-
`vide considerable improvement in tolerability com-
`pared to other PG analogues, but is not as effective
`as the PGF._,01 tromethamine salt, PGFZu—IE, 15-pro-
`pionate-PGFQa—IE, PhXA34, or PhXA41.10a
`The 17-phenyl substituted PGFM analogues
`(PhXA34 and latanoprost) provide the most accept-
`able separation between ocular hypotensive efficacy
`and adverse external ocular side effects. Latanoprost
`is the more active 15 R-epimer of PhXA34.
`Latanoprost is approximately two times as potent as
`PhXA34. It is more effective and at least 20 times
`
`more potent than isopropyl unoprostone.” None
`of the PG analogues that have been tested in clini-
`cal trials, even those that cause an initial rise in IOP
`
`and severe external ocular side effects, has produced
`intraocular inflammatory effects.
`
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`INITIAL CLINICAL STUDIES
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`S67
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`The studies reviewed in this article demonstrate
`
`that the hypotensive efficacy of PGs can be sepa-
`rated from their adverse ocular surface side effects
`
`by appropriate modification of their chemical struc-
`ture.
`
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`Surv Ophthalmol 41 (Suppl 2) February 1997
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`The authors wish to thank Dr. Laszlo Bito for his valuable
`comments in reviewing this manuscript and Dr. Bahram Resul
`for his help in preparing the figure.
`Supported in part by the Gifford Laboratory Fund, Omaha,
`Nebraska.
`Reprint address: Carl B. Camras, MD, Department of Oph—
`thalmology, University of Nebraska Medical Center, 600 South
`42nd Street, Omaha, NE 68198—5540.
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