IZBA - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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IZBA - Scientific Information

Manufacture: Alcon
Country: Canada
Condition: Intraocular Hypertension
Class: Ophthalmic glaucoma agents
Form: Eye drops (ophthalmic)
Ingredients: Travoprost (Travoprost), Polyquantemium-1, Boric acid, Hydrochloric acid and/or Sodium hydroxide (to adjust pH), Mannitol, Polyoxyethylene hydrogenated castor oil 40 (HCO-40), Propylene glycol, Purified water and Sodium chloride.

Pharmaceutical Information

Drug Substance

Proper Name: Travoprost
Chemical Name: [1R-[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid, 1-methylethylester
Molecular formula : C26H35F3O6
Molecular mass:  500.55
Structural formula:
Physicochemical properties: Colourless to light yellow, clear to slightly opalescent oil. Solubility in water measured as about 44 ppm. Solubility in 0.2% phosphate buffer, pH 7.04 measured at 41 ppm. Solubility of travoprost in methanol, octanol, chloroform and acetonitrile exceeded 10% w/v.
pH: Travoprost has such low solubility in water;, it is not possible to prepare aqueous solution that would give a meaningful pH value.

Clinical Trials

In three controlled clinical studies, with durations from 6 to 12 months (C-97-71, C-97-72 and C-97-79), patients with open-angle glaucoma or ocular hypertension were treated once daily in the evening with Travatan* (travoprost ophthalmic solution, 0.004%) (BAK- preserved). Travatan* demonstrated 6.7 to 9.0 mmHg reduction in IOP. Stable diurnal IOP reductions were achieved as early as 2 weeks after initiation of therapy and were maintained over the 6 to 12 month treatment period.

In a multicentre, randomized, double-masked trial (C-97-73), patients with mean baseline IOP of 24 to 26 mmHg on Timoptic* 0.5% BID, who were treated with Travatan* (BAK-preserved) dosed QD adjunctively to TIMOPTIC* 0.5% BID, demonstrated 6 to 7 mmHg additional reductions in IOP.

There are no plasma interactions with the concomitant administration of travoprost and timolol.

Table 1 summarizes the demographic characteristics of the population included in the clinical trials described above, and Table 2 summarizes the efficacy results of these studies.

Table 1: Summary of Patient Demographics for Clinical Trials Related to Specific Indication
Study # Trial design Dosage, route of administration and duration Study subjects (N) Mean age (Range) Gender (M/F)
C-97-71 Randomized, triple masked, multi-centre, parallel group, active control in patients with open-angle glaucoma or ocular hypertension 1 drop QD of placebo (8AM) + 1 drop QD (8PM) travoprost 0.004% or 0.0015%,;
1 drop QD of placebo (8AM) + 1 drop QD (PM) latanoprost 0.005%;
1 drop BID of TIMOPTIC 0.5% (8AM and 8 PM).

12 months.
787 64.2 years
(22-94)
392 M
395 F
C-97-72 Randomized, triple masked, multi-centre, parallel group, active control in patients with open-angle glaucoma or ocular hypertension 1 drop QD of placebo (8AM) + 1 drop QD (8PM) travoprost 0.004% or 0.0015%;
1 drop of TIMOPTIC 0.5% (8AM and 8PM);

6 months.
594 63.7 years
(21-91)
293 M
301 F
C-97-73 Randomized, multi-centre, triple-masked, vehicle-controlled, parallel group study in patients with open angle glaucoma or ocular hypertension who were uncontrolled after a 3-week run-in on TIMOPTIC 0.5% dosed BID. 1 drop QD (8PM) of travoprost 0.004% or 0.0015% + 1 drop BID of open-label TIMOPTIC 0.5% (8AM and 8PM);
1 drop QD (8PM) of placebo plus 1 drop BID of open-label TIMOPTIC 0.5% (8AM and 8PM).

6 months.
410 63.7 years
(11-89)
180 M
230 F
C-97-79 Randomized, multi-centre, triple masked, active controlled, parallel group study in patients with open angle glaucoma or ocular hypertension 1 drop QD of placebo (9AM) + 1 drop QD (9PM) travoprost 0.004% or 0.0015%;
1 drop BID of TIMOPTIC 0.5% (9AM and 9PM)

9 months.
572 63.3 years
(31-88)
284 M
288 F
C-01-74 Randomized, double-masked, multi-centre, parallel group, active-controlled in patients with open-angle glaucoma or ocular hypertension 1 drop QD of placebo (9 AM) + 1 drop QD (9PM) travoprost 0.004%;
1 drop QD of latanoprost/timolol 0.5% (9AM) + 1 drop QD of placebo (9PM).

6 weeks.
106 68.0 years
(34-86)
46 M
60 F

QD = once daily

Table 2: Mean Baseline IOP and Mean Change from Baseline IOP Measurements1
Study (Duration) Baseline mean IOP (mmHg) Mean IOP change from baseline (mmHg)
8 AM 10 AM 4 PM 8 AM 10 AM 4 PM
C-97-71
Travatan* 26.8 25.2 24.6 -7.6 -7.4 -6.9
Timolol 26.9 25.3 24.6 -6.7 -6.1 -5.3
Latanoprost 26.9 25.2 24.9 -7.7 -6.9 -6.3
C-97-72
Travatan* 27.3 25.7 25.1 -7.6 -7.2 -7.0
Timolol 27.4 25.8 25.4 -6.8 -6.0 -5.1
C-97-73
Travatan* / timolol 26.0 24.5 24.6 -6.8 -6.4 -6.0
Timolol 26.4 24.8 24.4 -2.6 -1.8 -1.6
C-97-79a
Travatan* 27.4 26.5 25.6 -8.8 -8.7 -8.2
Timolol 27.0 26.2 25.1 -7.7 -7.5 -6.6
C-01-74b
Travatan* 25.3 -- 24.3 -6.9 -- -6.8
latanoprost / timolol 24.6 -- 23.9 -6.4 -- -6.1

1 Least squares means from repeated measures ANOVA model

aC-97-79 IOP measurements were taken at 9AM, 11AM and 4PM.

bC-01-74 IOP measurements were taken at 9AM and 5PM. No statistical comparisons of treatments were carried out.

Study C-11-034 was designed to demonstrate equivalence of Izba* (POLYQUAD* preserved) to Travatan* (BAK-preserved), with both dosed once daily in the evening in patients with open-angle glaucoma or ocular hypertension. Overall, 864 patients were enrolled and randomized to 1 of 2 treatment groups: Izba* (POLYQUAD* preserved) or Travatan* (BAK-preserved). Of the 864 patients enrolled, 860 patients were evaluable for intent to treat analysis, 851 patients were evaluable for per protocol analysis and 863 were evaluable for safety (Table 3).

Table 3: Summary of Patient Demographics for Study C-11-034 in Patients with Open-Angle Glaucoma or Ocular Hypertension
Study # Trial design Dosage, route of administration and duration Study subjects (n) Mean age (Range) for Safety Dataset Gender (M/F)
C-11-034 (pivotal study) Multicentre, double-masked, randomized, active-controlled, 2-
arm, parallel-group, equivalence study
Travoprost 0.003% Solution
1 drop QD
8 PM
Topical ocular
442 65.2 years Male = 348
Female = 515
Travoprost 0.004% BAK,
1 drop QD
8 PM
Topical ocular
422

Primary and Supportive Efficacy Endpoints for Study C-11-034

The primary efficacy parameter was IOP at Week 2, Week 6 and Month 3 for each assessment time point (8AM, 10AM and 4PM).

Supportive efficacy included:

  • IOP change from baseline and IOP percent change from baseline at each visit (Week 2, Week 6 and Month 3) and assessment time point (8 AM, 10 AM and 4 PM),
  • the percentage of patients who achieved a target IOP level <18 mmHg at each visit and assessment time point, and
  • the percentage of patients who achieved IOP lowering of at least 30% from baseline at each visit and assessment time point.

Study Results

Primary Efficacy Results

The IOP-lowering efficacy of Izba* was equivalent to Travatan* at all on-therapy study visits and assessment time points. In the primary efficacy analysis, in order to conclude equivalence, the 2-sided 95% CI for the difference in IOP between treatment groups must have been within ± 1.5 mmHg at each of the 3 assessment time points (8 AM, 10 AM, and 4 PM) for each on-therapy visit (Week 2, Week 6 and Month 3). The least squares mean treatment group differences ranged from -0.3 to 0.0 mmHg with CIs ranging from -0.7 to 0.4 mmHg (Table 4). Thus, equivalence was met since all 9 of the assessments had CIs that were entirely within the pre-specified ± 1.5 mmHg margins. Further, all 9 of the assessments had CIs that were entirely within a ± 1.0 mmHg margin.

Table 4: Comparison of Mean IOP (mmHg) at Week 2, Week 6, and Month 3 (C-11-034 – Intent-to-Treat Data)
Visit Time Point Izba* Travatan* Mean Differencea (95% CI)
N Mean (SE) N Mean (SE)
Week 2 8 AM 442 19.4 (0.16) 416 19.5 (0.17) -0.1 (-0.5, 0.3)
10 AM 442 18.6 (0.16) 416 18.6 (0.16) -0.0 (-0.4, 0.4)
4 PM 442 18.0 (0.16) 416 18.3 (0.16) -0.3 (-0.7, 0.1)
Week 6 8 AM 439 19.3 (0.16) 413 19.3 (0.17) -0.0 (-0.4, 0.4)
10 AM 440 18.5 (0.16) 413 18.6 (0.17) -0.1 (-0.5, 0.3)
4 PM 440 18.0 (0.16) 413 18.1 (0.17) -0.2 (-0.6, 0.2)
Month 3 8 AM 432 19.2 (0.17) 408 19.3 (0.18) -0.1 (-0.5, 0.3)
10 AM 432 18.3 (0.17) 408 18.6 (0.18) -0.3 (-0.7, 0.1)
4 PM 431 18.0 (0.16) 408 18.0 (0.17) 0.0 (-0.4, 0.4)

Izba* = Travoprost 30 μg/mL eye drops, solution preserved with POLYQUAD*

Travatan* = Travoprost 40 μg/mL eye drops, solution preserved with BAK

SE = Standard Error; CI = Confidence Interval

aEstimates based on least squares means derived from a statistical model that accounts for correlated IOP measurements within patient where site and actual 8 AM baseline IOP stratum are in the model.

Supportive Efficacy Results

For each supportive efficacy endpoint, analysis provided no evidence of difference in IOP-lowering efficacy between Izba* and Travatan*.

The mean changes and percent changes in IOP from baseline to each study visit and assessment time point revealed no marked differences between treatment groups. The mean reductions in IOP within the Izba* group ranged from 7.1 to 8.2 mmHg; the mean reductions in IOP within the Travatan* group ranged from 7.1 to 8.4 mmHg (Figure 1). The percent reductions in IOP from baseline to each study visit and assessment time point ranged from 28.4% to 30.7% (Table 5). The percent reductions in IOP were similar across treatment groups at each individual assessment time point, and did not vary markedly from Week 2 to Week 6 or Month 3 in either treatment group. These results are consistent with and supportive of the primary efficacy conclusion that the two study drugs are equivalent.

Figure 1: Means and 95% Confidence Intervals for IOP Changes from Baseline (mmHg) by Visit (Intent-to-Treat Data)

Table 5: Descriptive Statistics for IOP Percent Change from Baseline (mmHg) by Visit (Intent-to-Treat Data)
Visit Izba* Travatan*
8 AM 10 AM 4 PM 8 AM 10 AM 4 PM
Week 2 N 442 442 442 416 416 416
Mean -29.7 -28.4 -28.7 -29.9 -29.3 -28.5
SD 10.67 10.97 11.43 11.33 11.44 11.55
(Min, Max) (-58, 0) (-61, 11) (-59, 9) (-60, 4) (-63, 9) (-59, 5)
95% CI (-30.7, -28.7) (-29.4, -27.4) (-29,7, -27.6) (-31.0, -28.8) (-30.4, -28,3) (-29.6, -27.4)
Week 6 N 439 440 440 413 413 413
Mean -30.3 -28.9 -28.8 -30.8 -29.4 -29.1
SD 10.78 10.89 11.35 11.36 11.36 11.11
(Min, Max) (-61, 14) (-62, 8) (-63, 4) (-65, 8) (-59, 14) (-57, 8)
95% CI (-31.3, -29.3) (-30.0, -27.9) (-29.9, -27.7) (-31.9, -29.7) (-30.5, -28.3) (-30.2, -28.0)
Month 3 N 432 432 431 408 408 408
Mean -30.7 -29.5 -28.5 -31.0 -29.5 -29.4
SD 11.29 11.44 11.48 10.93 11.50 11.37
(Min, Max) (-61, 30) (-59, 8) (-63, 9) (-60, 11) (-64, 25) (-64, 17)
95% CI (-31.7, -29.6) (-30.6, -28.5) (-29.6, -27.4) (-32.1, -30.0) (-30.6, -28.4) (-30.5, -28.3)

Izba* = Travoprost 30 μg/mL eye drops, solution preserved with POLYQUAD*

Travatan* = Travoprost 40 μg/mL eye drops, solution preserved with BAK

No marked differences between treatment groups were noted based upon the number and percentage of patients with IOP measurements less than 18 mmHg (Table 6). Approximately 33% to 55% of the patients had an IOP measurement below 18 mmHg during the study. While the percentages of patients whose IOP measurements were below this threshold varied across study visits and assessment time points, no marked differences were noted between treatment groups at any specific assessment. In both groups, the relevant percentages increased throughout the day, but did not vary substantially from Week 2 to Month 3.

Table 6: Number and Percentage of Patients with IOP <18 mmHg by Visit and Time Point (Intent-to-Treat Data)
  Izba* Travatan*
8 AM 10 AM 4 PM 8 AM 10 AM 4 PM
Total N (%) Total N (%) Total N (%) Total N (%) Total N (%) Total N (%)
Week 2 442 147
(33.3)
442 208
(47.1)
442 237
(53.6)
416 153
(36.8)
416 187
(45.0)
416 216
(51.9)
Week 6 439 172
(39.2)
440 195
(44.3)
440 240
(54.5)
413 156
(37.8)
413 181
(43.8)
413 218
(52.8)
Month 3 432 167
(38.7)
432 211
(48.8)
431 231
(53.6)
408 154
(37.7)
408 191
(46.8)
408 214
(52.5)

Izba* = Travoprost 30 μg/mL eye drops, solution preserved with POLYQUAD*

Travatan* = Travoprost 40 μg/mL eye drops, solution preserved with BAK

No marked differences between treatment groups were noted based on the number and percentage of patients with IOP-lowering of at least 30% relative to baseline (Table 7). No marked differences were noted between treatment groups when compared at an individual study visit and assessment time point. The greatest observed percentages were 53.7% in the Izba* group (also at 8 AM on Month 3). Overall, at every study visit and assessment time point, at least 43.9% of the patients in the Izba* group and 44.2% of the patients in the Travatan* group had a reduction in IOPs of at least 30% relative to baseline

Table 7: Number and Percentage of Patients with IOP Lowering of at Least 30% from Baseline by Visit and Time Point (Intent-to-Treat Data)
  Izba* Travatan*
8 AM 10 AM 4 PM 8 AM 10 AM 4 PM
Total N (%) Total N (%) Total N (%) Total N (%) Total N (%) Total N (%)
Week 2 442 219
(49.5)
442 194
(43.9)
442 208
(47.1)
416 197
(47.4)
416 201
(48.3)
416 (44.2)
Week 6 439 232
(52.8)
440 200
(45.5)
440 196
(44.5)
413 216
(52.3)
413 206
(49.9)
413 (47.5)
Month 3 432 232
(53.7)
432 228
(52.8)
431 192
(44.5)
408 222
(54.4)
408 204
(50.0)
408 (48.3)

Izba* = Travoprost 30 μg/mL eye drops, solution preserved with POLYQUAD*

Travatan* = Travoprost 40 μg/mL eye drops, solution preserved with BAK

Detailed Pharmacology

That pharmacology, safety pharmacology, pharmacokinetic and toxicological attributes of travoprost in non-clinical models has been extensively characterized. The non-clinical assessment of travoprost is based upon the already established non-clinical profiles of the active drug substance relative to ocular safety, local tolerance and potential systemic exposure.

Human Data

Pharmacodynamics

In Vitro Studies

In vitro protein binding of AL-5848, the active metabolite of travoprost, has been studied in human plasma. Binding of AL-5848 to plasma proteins was moderate (80%) over a 10,000-fold concentration range.

Pharmacokinetics

Phase I trials with travoprost 0.004% (BAK-preserved) or timolol 0.5% ophthalmic solutions were conducted to fully characterize the steady-state plasma pharmacokinetics of travoprost and AL-5848 in healthy subjects (C-99-08) and male Japanese (C-00-15) subjects, as well as in patients with renal (C-99-97) or hepatic (C-005-05) impairment. Studies C-99-08 and C-00-15 involved once-daily topical ocular administration of either travoprost 0.004% (BAK-preserved) or travoprost 0.0015% ophthalmic solutions for both eyes for 7 days. The renal (C-99-97) and hepatic (C-00-05) impairment studies involved once-daily bilateral administration of travoprost ophthalmic solution, 0.004% (BAK-preserved) for 7 days. One controlled study (C-02-35) was conducted to determine plasma pharmacokinetics of AL-5848 and timolol, when the travoprost/timolol ophthalmic solution was administered compared to when travoprost 0.004% (BAK-preserved) and timolol 0.5% ophthalmic solutions were administered independently, following a once-daily dosing regimen for 3 days.

A summary of plasma pharmacokinetic parameters of the travoprost active acid metabolite (AL-5848) across Phase I studies is presented below (Table 8).

Table 8: Plasma Pharmacokinetics of AL-5848 across Phase I Studies Following Topical Ocular Dosing with Travoprost Ophthalmic Solution, 0.004% BAK-preserved)
Study Treatment Cmax
(pg/mL)
Tmax
(hr)
T1/2
(hr)
N
C-99-08 Travoprost, 0.004%
(BAK-preserved)
15 ± 5 0.26 ± 0.12 ND 16
C-00-05 Travoprost, 0.004%
(BAK-preserved)
21 ± 8 0.27 ± 0.16 0.75 ± 0.23a 31
C-99-97 Travoprost, 0.004%
(BAK-preserved)
14 ± 3 0.19 ± 0.04 ND 4
C-00-15 Travoprost, 0.004%
(BAK-preserved)
15 ± 6 0.18 ± 0.06 ND 7
C-02-35 Travoprost, 0.004%
(BAK-preserved)
16 ± 4 0.42 ± 0.14 ND 3

Values represent means ± standard deviation

N Number of pharmacokinetic profiles with at least one quantifiable assay value.

ND Not determined because of insufficient data for calculation.

a Mean t1/2 based on values from 22 subjects.

In approximately two-thirds of subjects administered travoprost ophthalmic solution, 0.004% (BAK-preserved) across the 5 studies, no quantifiable AL-5848 concentrations were measured. In about 70% of the profiles, plasma concentrations were below the assay Limit Of Quantification (LOQ) (<10 pg/mL). In those pharmacokinetic profiles with quantifiable concentrations of AL-5848, the mean Cmax for travoprost acid metabolite (AL-5848) was comparable across the 5 studies (ranging from 15 to 21 pg/mL). In all but one subject for whom quantifiable plasma concentrations of AL-5848 were observed, the Cmax was observed within 30 minutes after dosing. One subject in Study C-00-05 had a Tmax value of 45 minutes. A total of 22 pharmacokinetic profiles, representing 14 subjects, had sufficient quantifiable concentrations of AL-5848 to estimate a t1/2 which had a mean value of 45 ± 14 minutes (0.75 ± 0.23 hours). The elimination of AL-5848 from plasma was rapid, resulting in residual levels that were generally below the assay LOQ (10 pg/mL) within one hour post-dose.

Single- and multiple-dose pharmacokinetics of travoprost were assessed in a total of 5 Phase I studies. The plasma concentrations of AL-5848 were similar after the single- and multiple-dose administration across all 5 studies.

A comparison of pharmacokinetic results for AL-5848 after the first dose and the last dose (steady-state) of travoprost ophthalmic solution, 0.004% (BAK-preserved) in healthy subjects and Japanese subjects, and in patients with renal or hepatic impairment, dosed once-daily for 7 days, showed a similar pattern of low systemic exposure across these 4 studies (C-99-08, C-99-97, C-00-05, C-00-15). The majority of plasma concentrations were below the assay LOQ (10 pg/mL). Furthermore, there was no evidence of drug accumulation after repeated administration of travoprost ophthalmic solution, 0.004% (BAK-preserved) across studies, including those studies of patients with renal and hepatic impairment.

The low systemic concentrations of AL-4858 observed in Study C-02-35 after repeated ocular administration (3 days) of Travoprost 0.004% BAK or travoprost/timolol ophthalmic solution were also consistent with those observed in healthy subjects (C-99-08) and Japanese (C-00-15) subjects and patients with renal (C-99-97) or hepatic (C-00-05) impairment. There were no apparent differences in the concentrations of AL-5848 between Day 1 and Day 3, indicating no accumulation of drug, and there were no observable differences between treatments.

Animal Data

Pharmacodynamics

In Vivo Studies

In the cynomolgus monkey, instillation of a single dose of travoprost reduced IOP in a dose-related fashion, with a peak reduction of 30% with a 0.3 μg dose. Once daily dosing provided IOP reductions for a 24 hour period.

Table 9: Reduction of IOP following BID Travoprost (AL-6221) in Lasered Cynomolgus Monkeys
Dose (μg) Baseline
IOP
Dose number/hour after dose
Percent ± SEM
(mmHg ± SEM)
[Vehicle]1 (mmHg) 1/22 1/4 1/6 4/16 5/2 5/4 5/6
0.1 [P/P] 36.8 1.8 ± 6.4
(1.7 ± 2.6)
7.7 ± 6.8
(3.9 ± 3.0)
9.3 ± 8.1
(4.8 ± 3.8)
16.94 ± 4.3
(6.8 ± 1.9)
22.74 ± 5.8
(9.3± 3.1)
21.84 ± 6.8
(9.2 ± 3.5)
15.3 ± 7.6
(6.6 ± 3.6)
Vehicle 41.4 16.4 ± 8.3
(8.4 ± 5.1)
19.0 ± 8.4
(10.2 ± 2.6)
20.7 ± 7.7
(10.6 ± 3.0)
8.1 ± 1.9
(3.8 ± 6.1)
14.7 ± 9.8
(8.4 ± 3.3)
16.9 ± 8.7
(9.0 ± 3.4)
9.4 ± 9.0
(6.4 ± 3.0)
0.3
[T.N.]
41.6 19.03 ± 4.1
(8.5 ± 1.9)
15.03 ± 2.5
(6.6 ± 1.3)
18.53 ± 3.0
(8.2 ± 1.5)
18.43 ± 5.9
(8.4 ± 2.8)
31.23 ± 3.7
(13.5 ± 2.1)
30.33 ± 3.8
(13.2 ± 2.0)
26.63 ± 3.6
(11.6 ± 1.9)
Vehicle 40.6 6.5 ± 4.7
(3.2 ± 2.5)
9.2 ± 5.7
(4.0 ± 3.7)
1.9 ± 4.5
(9.0 ± 3.8)
6.64 ± 2.6
(2.6 ± 4.3)
13.34 ± 4.8
(5.4 ± 4.0)
16.4 ± 4.3
(7.2 ± 2.0)
14.6 ± 7.2
(7.0 ± 1.6)
0.3
[P/P]
36.8 19.54 ± 3.7
(7.7 ± 2.1)
25.74 ± 5.0
(10.8 ± 3.4)
22.14 ± 5.9
(9.2 ± 3.4)
29.94 ± 3.7
(11.9 ± 2.4)
28.64 ± 5.2
(11.9 ± 3.2)
28.14 ± 5.7
(11.9 ± 3.4)
20.74 ± 5.3
(9.0 ± 3.1)
Vehicle 34.7 7.2 ± 4.8
(3.0 ± 4.3)
6.1 ± 7.0
(3.5 ± 2.9)
5.1 ± 8.1
(3.5 ± 2.4)
2.6 ± 5.6
(1.5 ± 4.5)
1.1 ± 6.0
(1.4 ± 3.9)
4.6 ± 7.5
(2.7 ± 3.7)
+6,8 ± 6.7
(+2.7 ± 4.2)

1P/P = phosphate buffered saline with polysorbate 80; TN = Tears Naturale

2BID dosing at 0900 and 1700 hours; Dose number/hour after dose

3p<0.01

4p<0.05

In one cross-over study, the optic nerve head blood flow (ONHBF) was significantly increased 13.4% (± 3.9%) in 15 Dutch-belted rabbits following once daily topical ocular dosing with travoprost for one week. Systemic circulatory parameters were not affected by drug treatment.

In a safety study in naïve dark-adapted Dutch-belted rabbits, a single subcutaneous dose of vehicle (1.6 mL/kg) or 100 μg/kg of travoprost produced no significant changes in the peak amplitudes or latencies of the A-wave or the B-wave of the flash electroretinogram (ERG) measured at 1 hour or 1 week after dosing. This suggests that travoprost produces no functional changes in the photoreceptors or the inner retinal layers of the eye at a dose approximately 2,000 times higher than the maximum recommended clinical dose of 0.046 μg/kg/day.

In Vitro Studies

Receptor binding affinity was compared for the acid forms of travoprost and latanoprost. The two acid prostaglandin analogues had a high affinity binding for the FP-receptors (bovine corpus luteum membranes). Receptor interaction appeared to be at a single binding site. There was a low affinity for the other prostaglandin receptors. The parent free acid of travoprost is over 60-fold les potent in binding to other receptors. Travoprost demonstrates higher potency and higher selectivity for the FP receptor compared to latanoprost.

Table 10: Receptor affinity data for Travoprost and Latanoprost free acids (Ki, nM)
  DP receptors EP3 receptors EP4 receptors FP receptors IP receptors TP receptors
Travoprost free acid 46000 3500 12000 52 90000 120000
Latanoprost free acid 26000 7900 9000 92 >90000 61000
Prostaglandin Functional Assays

Travoprost free acid was a potent and fully efficacious agonist in stimulating phophoinositide (PI) turnover in Swiss 3T3 cells expressing a FP receptor. In contrast, latanoprost acid had lower potency than the travoprost free acid and was a partial agonist in the system.

Table 11: Second Messenger Study: Potency & Efficacy
  FP PI turnover DP cyclase stim EP2 stim
Travoprost free acid 4 nM (Emax = 100%) Inactive Inactive
Latanoprost free acid 27 nM (Emax = 75%) Inactive Inactive

Travoprost acid did not demonstrate affinity for a panel of over 32 different non-prostanoid receptors, including muscarinic, alpha-adrenergic, beta-adrenergic, and endothelin receptors at concentrations up to 10 μM.

Safety Pharmacology

Major findings from safety pharmacology studies with travoprost (AL-6221) or its free acid, AL-5848, were consistent with known pharmacology of PFGα and its analogues, a small to moderate increase in cardiac contractility in dogs, a dose-related increase in GI propulsion in mice, and contractions in estrogen-primed rat uterus. The increases in cardiac contractility and increase in GI propulsion were observed at doses that were approximately 28 to 833 times the recommended clinical dose (0.036 μg/kg/day) of travoprost ophthalmic solution, 0.003%. While the lowest concentration that produced a measureable increase in contractions in isolated uterus strips was about 6-fold higher than the highest concentration measured in humans after a dose of 0.048 μg/kg/day. Additionally, the concentration of travoprost that can actually reach the uterus after the therapeutic use of travoprost ophthalmic solution, 0.003% will be substantially lower than the concentration of travoprost bathing isolated rat uterus strips in this study.

Based on the results of the safety pharmacology studies, and the established safety of Travatan* (travoprost, 0.004%; BAK-preserved) and Travatan*Z (travoprost 0.004%; sofZia-preserved), the safety margin for Izba* administered by topical ocular route is considered sufficiently wide to preclude any concerns of significant functional adverse events in humans.

Pharmacokinetics

Following topical ocular administration of travoprost ophthalmic solution, 0.004% (BAK-preserved) to rabbits, AL-6221 was rapidly absorbed into the eye and its isopropyl ester hydrolyzed to the pharmacologically active metabolite AL-5848. As a result, AL-5848 levels are substantially higher than AL-6221 levels. In the rabbit cornea and aqueous humor, the maximal concentrations of AL-5848 were 405 ng/g and 20.2 ng/g versus 32.9 ng/g and 0.820 ng/g for AL-6221, respectively. AL-5848 concentrations declined with half-lives of 1.2-1.4 hours in these tissues.

Studies in pigmented rabbits demonstrated that both AL-6221 and AL-5848 do not have a binding affinity for melanin pigmented ocular tissues.

Travoprost exhibits low oral bioavailability (< 3-6%). As a result, the pharmacokinetics of AL-5848 following subcutaneous doses of AL-6221 were determined in order to demonstrate the suitability of this route for use in Toxicology studies The results of these studies demonstrated dose proportionality (Cmax and AUC) and rapid distribution from the site (Tmax 20-40 minutes). The percent of dose absorbed from the subcutaneous depot was demonstrated to be high from radioactivity studies where approximately 96% of the dose was absorbed by 72 hours after dosing. These results demonstrated that the subcutaneous route provides suitable exposure in toxicology studies.

In rats, radioactivity distributes widely in the body following subcutaneous doses of 3H-AL-6221. Tissue concentrations after 14-daily 0.1 mg/kg doses were higher than after a single dose by approximately 3.5-fold. Radioactivity concentrations declined rapidly and after a single dose were below detection limits in most tissues by 24 hours. In contrast, after a multiple dose regimen, radioactivity concentrations were measurable to 168 hours. Highest concentrations of radioactivity were found in kidney, liver, lung and plasma which were typically 10-fold higher than in other tissues. Tissues with low levels of radioactivity included brain, testes, muscle and fat which had maximal levels approximately 50-fold lower than in kidney, liver, lung and plasma. Tissue concentrations declined rapidly with a profile similar to that in plasma. After Cmax, concentrations declined in a biphasic manner. . During the initial rapid decline, greater than 90% of radioactivity in most tissues was eliminated.

The percent of 3H-AL-5848 bound to human, monkey and rat plasma proteins was concentration independent over a wide range (0.01 – 100 ng/mL), similar between species and moderate at approximately 80%. As a result, drug-drug interactions involving protein binding are unlikely.

The metabolism of AL-6221/AL-5848 follows that of endogenous prostaglandins such as prostaglandin PG-F2α. The first step in this metabolic pathway involves oxidation of the 15-hydroxyl by cytosolic NAD+/NADP+ dependent prostaglandin 15-hydroxyl dehydrogenase. This is followed by reduction of the 13,14-double bond by a NADPH dependent 15-keto prostaglandin reductase, also a cytosolic enzyme. Cleavages of the carboxylic side chain then proceeds via mitochondrial beta- and endoplasmic reticulum gamma-oxidases.

Studies in rats showed that radioactivity from 3H-AL-6221 doses is rapidly excreted in urine and feces. Ninety-five percent of the dose was recovered in the excreta in the first 24 hours. After 168 hours, only about 0.3% remained in the carcass. The major route of excretion is by biliary excretion and fecal elimination (74%).

Radioactivity was observed in the milk of lactating rats following a 0.1 mg/kg subcutaneous dose of 3H-AL-6221. Maximal levels were observed at 6 hours which then declined to < 3% of those at Cmax by 24 hours which at this time were similar to those in maternal plasma (milk:plasma ratio 0.78).

Microbiology

Not applicable.

Toxicology

Acute Toxicity

Travoprost was demonstrated to have a low order of acute toxicity. No mortalities occurred in rats administered travoprost intravenously at a dose of 10 mg/kg/day (or in mice given up to 100 mg/kg/day (several magnitudes higher than the maximum recommended human ocular dose (MRHOD) of 0.03 mg/kg/day. No systemic effects were observed.

Ophthalmic solutions containing 0.004% travoprost (BAK-free) administered (one or two drops) to one eye, every half hour for ten doses on a single day resulted in no or only minimal to moderate ocular discomfort and demonstrated low irritation potential.

Repeated-Dose Sub-chronic, Chronic Toxicity

Repeated-dose systemic studies with travoprost were conducted in rats and mice with travoprost administered by the oral, intravenous, intraperitoneal, or subcutaneous routes. Study duration ranged from two weeks (mouse, oral) to six months (rat, subcutaneous). In the mouse, intravenous/intraperitoneal administration for up to 13 weeks had a NOAEL of 1000 µg/kg. In the rat, subcutaneous administration of 30 and 100 µg/kg for 6 months showed hyperostosis and fibrosis of bones examined (femur and sternum). Extramedullary hematopoiesis was observed in the liver and spleen. Decreases in red blood cell parameters were also observed. The bone, spleen, liver and hematological changes were not observed in cynomolgus monkeys receiving travoprost by topical ocular administration for one year.

Repeat-dose topical ocular studies with travoprost (BAK-preserved) in rabbits (up to 6 months) and cynomolgus monkeys (1 year), showed no signs of ocular irritation or systemic toxicity at doses of up to 0.01 or 0.012%, respectively, when travoprost was administered up to three times a day to one eye. There was an increase in iris pigmentation and appearance of irregular corneal surface in the 1-year monkey study (all groups). In addition, a widened palpebral fissure was observed in those monkeys receiving travoprost. This observation has been noted in primates administered travoprost or other prostanoids such as latanoprost or bimatoprost.

Topical ocular toxicity of travoprost ophthalmic solutions (POLYQUAD* preserved) was determined in a 3-month repeated-dose study in rabbits.

Table 12: Topical Ocular Repeated-Dose Studies Conducted with Travoprost Ophthalmic Solutions (POLYQUAD* preserved)
Animal (Species) / Duration Route No. of animals Frequency Dose Result
Rabbit (NZW) / 3 months Topical Ocular/ OU 5/sex/ group TID
TID
BID
BID
Vehicle
20 µg/mL
40 µg/mL
120 µg/mL
No significant toxicity

NZW=New Zealand White, TID=three times daily, BID=twice daily, OU=both eyes

No observed adverse effect level (NOAEL) is underlined.

There were no signs of ocular irritation and no significant effects on the intraocular pressure, corneal thickness or specular microscopy, no signs of systemic toxicity and no adverse clinical observations were observed. There were no significant alterations in clinical chemistry or histopathology, . A NOAEL for travoprost ophthalmic solution (POLYQUAD* preserved) was determined to be 120 µg/mL when administered twice daily per eye for 3 months.

Carcinogenesis

Two year bioassays, in which rats and mice were dosed with travoprost by subcutaneous injection at doses up to 100 micrograms/kg/day (>3000 times the MRHOD), revealed no evidence of carcinogenic effect.

Mutagenesis

Travoprost was not mutagenic in bacteria, in one mouse lymphoma assay, in the mouse micronucleus tests or in the rat chromosome aberration assay. In another mouse lymphoma assay, higher concentrations of travoprost were slightly mutagenic only in the presence of activation enzymes.

Reproduction and Teratology

Travoprost did not affect mating or fertility indices in male or female rats and mice at subcutaneous doses up to 10 μg/kg/day (>300 times the MRHOD). The mean number of corpora lutea was slightly reduced and an increase in post-implantation loss was detected at that dose, but was not affected at 3 μg/kg/day (100 times the MRHOD).

In teratology studies conducted in pregnant rats and mice, travoprost reduced fetal viability when administered daily during the period of major organogenesis at doses as low as 1.0 (mice) and 10 (rats) μg/kg/day (>30 and >300 times the MRHOD respectively) with the lowest no effect level at 0.3 μg/kg/day (10 times the MRHOD). The incidence of skeletal malformations was slightly increased in fetuses of rat dams receiving travoprost by subcutaneous injection at 10 μg/kg/day (>300 times the MRHOD), but not at 3 μg/kg/day (100 times the MRHOD). No fetal abnormalities were observed in mice at 1.0 μg/kg/day (>30times the MRHOD).

Pregnant rats dosed subcutaneously with up to 0.72 μg/kg/day from gestation Day 6 through lactation day 20 showed gestation length reduced in a dose related manner and the number of stillborn pups was increased. Surviving pup body weights were reduced. Pup development was affected as demonstrated by delayed static-righting reflex, eye opening and pinna detachment, delayed preputial separation and decrease in monitor activity parameters. The no-observed adverse effect level was 0.1 μg/kg/day (>3 times the MRHOD).