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Aqueous Humor Concentrations of Travoprost Free Acid and Residual Drug in Explanted Implants from Patients Administered a Travoprost Intracameral Implant
To determine the aqueous humor (AH) exposure to travoprost free acid (TFA) and the in vivo elution rate of travoprost over a 24-month period in subjects with open-angle glaucoma administered a travoprost intracameral implant, 75 µg.
Methods
In this prospective, single-center, open-label study, 210 subjects (7 cohorts of 30 subjects each) were administered a travoprost intracameral implant and followed for 3–24 months. At pre-determined timepoints (3, 6, 12, 15, 18, 21, and 24 months), AH was collected, a new implant was administered, and the prior implant removed. AH samples were assayed for TFA concentrations using a validated liquid chromatography-tandem mass spectrometry method. Explants were analyzed for remaining travoprost using a validated high-performance liquid chromatography method.
Results
Mean AH concentrations of TFA were 5.0, 3.7, 5.6, 2.0, 2.2, 3.8, and 3.3 ng/mL at 3, 6, 12, 15, 18, 21, and 24 months, respectively, post-administration. Mean percent travoprost remaining in explants was approximately 79%, 70%, 50%, 39%, 35%, 28%, and 16% at 3, 6, 12, 15, 18, 21 and 24 months, respectively, post-administration.
Conclusions
Concentrations of TFA in AH through month 24 were above the established efficacious concentration of 0.1 ng/mL for intracameral implants, indicating that adequate TFA levels were achieved to elicit maximal intraocular pressure (IOP)-lowering efficacy, and supported by low levels of IOP in subjects through 24 months. The remaining dose of travoprost in explants at 24 months (i.e., 16%) indicates the potential for efficacious drug delivery beyond 2 years.
Trial Registration Number
Clinical Trials.gov Identifier: NCT06582732 (31 August 2024: retrospectively registered).
Prior Presentation: Parts of this manuscript have been presented previously at the Association for Vision and Ophthalmology 2023 (New Orleans, LA, USA; 23–27 April 2023); at the Association for Vision and Ophthalmology 2024 (Seattle, WA, USA; 5–9 May 2024); and at the American Academy of Ophthalmology 2024 (Chicago, IL, USA; 18–21 October 2024).
Key Summary Points
Why carry out this study?
The aim of this study was to evaluate the aqueous humor concentrations of travoprost free acid and the remaining travoprost in implants from patients who had received an iDose® TR (travoprost intracameral implant) 75 µg.
Seven cohorts of 30 patients each were enrolled. At pre-determined timepoints (3, 6, 12, 15, 18, 21, 24 months) after receipt of the travoprost intracameral implant, we collected an aqueous humor sample, administered a new implant, and removed the prior implant.
What was learned from the study?
The concentration of travoprost in the aqueous humor at all timepoints through 24 months was above that established previously to be efficacious in lowering intraocular pressure.
We found that there was still residual travoprost (approximately 16% of the initial amount) in the implants at 24 months and deduced that the travoprost intracameral implant has the potential to deliver travoprost beyond 2 years.
We also observed that the intraocular pressure was well controlled through 24 months following receipt of a travoprost intracameral implant.
Introduction
Topical medications have traditionally been the most common initial intervention to lower intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). However, in recent years, earlier use of procedural-based interventions, such as selective laser trabeculoplasty, micro-invasive glaucoma surgery, and sustained-release drug delivery systems, has gained acceptance as a means to address the challenges associated with poor patient adherence in the medical management of glaucoma [1].
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Two such sustained-release drug delivery systems have been approved in the USA. One is Durysta, the bimatoprost intracameral implant, 10 µg (Allergan Inc., AbbVie Inc., Chicago, IL), which is a biodegradable implant that rests unanchored in the inferior iridocorneal angle. The other is iDose TR, the travoprost intracameral implant, 75 µg (Glaukos Corporation, Aliso Viejo, CA, USA), which is anchored through the trabecular meshwork into the sclera at the nasal iridocorneal angle.
The travoprost intracameral implant comprises a titanium reservoir, which contains 75 µg travoprost, an ethylene vinyl acetate membrane, which controls the release of travoprost and is held in place by a titanium cap, and a titanium anchor (Fig. 1). The implant is administered into the anterior chamber through a small, temporal clear corneal incision. Once the travoprost in the reservoir has been depleted, the delivery system is designed such that a new implant can be administered, and the previous implant removed.
Fig. 1
Travoprost intracameral implant showing the anchor and reservoir, ethylene vinyl acetate membrane, and cap (image on left) and fully assembled travoprost intracameral implant(image on right)
Travoprost, the active ingredient in the implant, is an isopropyl ester prodrug that is hydrolyzed by esterases in the cornea and other intraocular tissues to travoprost free acid [(+)-fluprostenol; TFA]. This biologically active free acid exhibits high binding affinity and high potency at the prostaglandin F (FP) receptor, as well as high selectivity for the FP receptor [2‐4]. Activation of the FP receptors in the ciliary muscle and scleral tissue increases production of matrix metalloproteinases; the resultant remodeling of the extracellular matrix within the ciliary body is believed to increase uveoscleral outflow [3, 5‐7]. FP receptors are also located on trabecular meshwork cells, and activation of these receptors by travoprost free acid may also promote trabecular outflow of aqueous humor [3]. The resultant increase in outflow of aqueous humor through both the uveoscleral and trabecular meshwork routes lowers IOP [8].
A phase 2 clinical trial demonstrated that the travoprost intracameral implant provided robust IOP-lowering and substantially reduced the need for adjunctive topical IOP-lowering medication for up to 36 months following administration [9].
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The current study was conducted to evaluate the concentrations of TFA in aqueous humor and the intracameral elution rate of travoprost in patients with OAG or OHT who were administered travoprost intracameral implant, 75 µg, and followed for up to 24 months. IOP and safety parameters also were evaluated in this study.
Methods
Study Design and Setting
This prospective, open-label study was conducted at a single site in Armenia between March 2021 and November 2023. The study was performed in accordance with International Council on Harmonisation for good clinical practices, the tenets of the Declaration of Helsinki, and regulations governing clinical trials in Armenia, and with approval of the relevant institutional review board/independent ethics committee (Ethics Committee of Ophthalmological Center named after S.V. Malayan, Yerevan, Armenia; approval date: 21 December 2019). Written informed consent was obtained from all patients prior to undertaking any study-related procedures.
Participants
Eligible patients were required to be ≥ 18 years. The study eye was required to have a diagnosis of OAG (primary, pseudoexfoliative, or pigmentary glaucoma) or OHT; be on ≤ 3 topical IOP-lowering medications; have a central corneal thickness of at least 440 μm but not exceed 620 μm; have normal angle anatomy as determined by gonioscopy with an absence of peripheral anterior synechiae or rubeosis; and have an open angle defined as Shaffer grade of III or IV at the planned site of administration. Both the study eye and fellow eye were required to have a best-corrected visual acuity (BCVA) of ≥ 16 Early Treatment Diabetic Retinopathy Study (ETDRS) letters read correctly at 4 m (i.e., better than 20/125 Snellen). The study eye could be phakic provided the lens did not have a visually significant cataract likely to require surgery during the study period or could be pseudophakic with a posterior chamber intraocular lens if uncomplicated cataract surgery had been performed at least 90 days prior.
Patients were excluded from study participation if the study eye had functionally significant visual field loss; had undergone prior incisional glaucoma surgery; had any active corneal inflammation or edema; had clinically significant corneal dystrophy or guttata; had significant corneal scars or irregularities; or had corneal opacities or disorders that inhibited visualization of the nasal angle. In addition, patients were excluded if the study eye had exhibited any retinal (e.g., proliferative diabetic retinopathy, central retinal artery occlusion, central retinal vein occlusion, neovascular age-related macular degeneration, advanced dry age-related macular degeneration) or optic nerve disorders; if the eye had previously experienced any clinically significant sequelae from trauma; or if there was any history of chronic ocular inflammatory disease or presence of active ocular inflammation (e.g., uveitis, iritis, iridocyclitis, retinitis, ocular herpes).
Finally, patients were excluded if the fellow eye was actively enrolled in the current trial or any other clinical trial; if the patient was a woman of childbearing potential who was pregnant or planning a pregnancy; if the patient had uncontrolled systemic disease, had an immunodeficiency disorder, had a known allergy, hypersensitivity or contraindication to prostaglandin analogs; was currently participating in another clinical trial or had participated in another within the prior 30 days; or had a change in an existing chronic systemic therapy that could substantially affect IOP or the study outcomes within the past 30 days or anticipated change in such therapy during the study duration.
Both eyes of the patient could be assessed for eligibility; however, only one eye (the study eye) was ultimately entered into the study. If both eyes qualified, the right eye was selected as the study eye.
Procedures and Assessments
At the screening visit, patients underwent the informed consent process, and demographic information, medical and surgical history, current ocular and systemic conditions, and medications were recorded. In addition, slit-lamp biomicroscopy (to assess the anterior structures of the eye, including crystalline lens status, and Shaffer grade), tonometry (to measure IOP), pachymetry (to measure corneal thickness), gonioscopy (to assess the angle anatomy), and dilated ophthalmoscopy (to assess the posterior structures of the eye, including optic nerve abnormalities and vertical cup-to-disc ratio) were performed. BCVA was measured through manifest refraction in each eye, and a pregnancy test was performed on women of childbearing potential.
Patients who met all of the inclusion criteria and none of the exclusion criteria were scheduled for their first operative visit and dispensed a topical fluoroquinolone or other broad-spectrum antibiotic to be administered in the study eye 4 times daily for at least 1 day preoperatively. Patients taking heparin were instructed to discontinue heparin 1 day prior to surgery, and patients on topical IOP-lowering medication were advised to discontinue their medication beginning the morning of their first operative visit.
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Patients underwent administration of a travoprost intracameral implant at the first operative visit at which time they were assigned to a cohort in sequential order of study entry. Each individual cohort was required to have the complete number of 30 patients enrolled prior to assigning patients to the next cohort. The order of cohorts, duration of initial assessment period prior to readministration, and cohort-specific post-operative visits are presented in Table 1. The sequencing of cohorts, with the first cohort assigned to undergo exchange at month 12, was designed to obtain month 12 data as early as possible in the trial.
Table 1
Cohorts in the study
Cohort ordera
Timeb (months)
Number of patients entered
Cohort-specific post-operative visitsc
1
12
30
Months 6, 12
2
3
30
Month 3
3
6
30
Month 6
4
24
30
Months 6, 12, 18, 24
5
21
30
Months 6, 12, 18, 21
6
18
30
Months 6, 12, 18
7
15
30
Months 6, 12, 15
aOrder of enrollment into the study
bDuration from the time of administration of implant at visit 2 (first operative day 0) until the exchange procedure and collection of aqueous humor sample
cAll patients had visits at post-operative day 1, day 10, week 4, pre-exchange, and post-exchange day 1, day 10, and week 4
On the day of the first operative visit, an additional drop of topical antibiotic was administered to the study eye 30 min preoperatively, a drop of pilocarpine was administered, the angle and target implant location were visually confirmed, and a treatment kit was obtained. Anesthetic (topical eye drops and/or intracameral lidocaine) was administered to the study eye, and the travoprost intracameral implant was administered. Intra-operative or post-operative adverse events in the study eye were recorded. The patient was dispensed a topical ocular nonsteroidal anti-inflammatory drug to be administered for 1 week, along with their topical antibiotic.
Post-operatively, depending on the cohort to which the patient was assigned, there were 8–13 follow-up visits over a 4- to 25-month period.
Follow-up visits for all cohorts occurred on day 1, day 10, and week 4. At all three follow-up visits, the patient’s medical status and concomitant medications were updated, if applicable, and study eye adverse events were recorded. In addition, visual acuity was measured [pinhole Snellen visual acuity (VA) at days 1 and 10; ETDRS BCVA at week 4), slit-lamp biomicroscopy was performed, and IOP was measured. At week 4, a gonioscopic examination also was performed.
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Depending on the cohort, patients who remained ongoing in the trial may have had a follow-up visit at one or more of the following timepoints: month 6, month 12, and month 18. At these visits, the patient’s medical status and concomitant medications were updated, if applicable, study eye adverse events were recorded, VA was measured (ETDRS BCVA), slit-lamp biomicroscopy was performed, IOP was measured, and a gonioscopic examination was performed.
An additional visit (pre-exchange visit, at month 3, 6, 12, 15, 18, 21, or 24) occurred within 10 days prior to the second operative visit (“exchange”) and included the following: the patient’s medical status and concomitant medications were updated, if applicable, study eye adverse events were recorded, visual acuity was measured (ETDRS BCVA), slit-lamp biomicroscopy was performed, IOP was measured, and a gonioscopic examination was performed.
The second operative visit (“exchange”) occurred in accordance with the patient’s cohort assignment and was aimed at assessing the 12-month data as soon as feasible (i.e., at month 12, month 3, month 6, month 24, month 21, month 18, or month 15). As with the first operative visit, patients administered a topical antibiotic 4 times daily for at least 1 day preoperatively in the study eye, and those taking heparin were instructed to discontinue heparin 1 day prior to surgery. An additional drop of antibiotic was administered 30 min preoperatively, a drop of pilocarpine was administered, and the angle and target implant location were visually confirmed. Thereafter, a treatment kit was obtained, anesthetic was administered to the study eye, an anterior chamber aqueous humor sample was collected, the second implant was administered, the first implant was explanted, and any study eye intra-operative or post-operative adverse events were recorded. The patient was dispensed a topical ocular nonsteroidal anti-inflammatory drug to be administered for 1 week, along with their topical antibiotic.
Post-exchange follow-up visits for all cohorts occurred on day 1, day 10, and week 4. Procedures at these visits were identical to those performed on day 1, day 10, and week 4 following the initial administration.
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Although of clinical interest, given that patients in the study were followed for up to 24 months and underwent an implant exchange, endothelial cell density and visual field data were not collected since the primary objective of the study was to obtain pharmacokinetic data.
Collection of Aqueous Humor and Bioanalytical Analysis
Aqueous humor samples were collected at the second operative visit (i.e., at month 3, 6, 12, 15, 18, 21 or 24) prior to administration of a new implant and removal of the previous implant.
After making a limbal paracentesis incision, a 150-µL aqueous humor sample was collected using a sterile 27- to 31-gauge needle attached to a 1-mL tuberculin syringe. The sample was split into two 75-µL aliquots (a primary and backup) and stored at − 20 °C or below until shipment to the bioanalytical lab for bioanalysis. Samples were maintained frozen at − 20 °C or below during shipment.
Aqueous humor samples were assayed in a masked manner by an independent bioanalytical laboratory (Pharmaron, Exton, PA, USA). A deuterated analog of TFA was added to samples as an internal standard, and the samples were then extracted with 50:50 acetonitrile:water. Two liquid chromatography-tandem mass spectrometry (LC–MS/MS) methods were used during the analysis of aqueous humor samples. Samples from cohorts 1 to 3 (patients whose implants were exchanged at month 3, 6, or 12, respectively) were analyzed using an API 4000 LC–MS/MS system (Sciex, Framingham, MA, USA). Chromatography was performed on a Phenomenex Synergi 4 μm Polar-RP, 80A, 50 × 2.0-mm column and analyzed by electrospray ionization mass spectrometry in the negative ion mode. A gradient program (0.1% formic acid in H2O as mobile phase A, 0.1% formic acid in acetonitrile as mobile phase B, and a flow rate of 0.500 mL/min) was used to elute TFA and the internal standard. The range of the assay was 0.500–200 ng/mL using a 25-μL aliquot of sample.
In order to increase the sensitivity of the assay, samples from cohorts 4 to 7 (i.e., patients whose implants were exchanged at month 15, 18, 21, or 24 respectively) were analyzed using an API 6500 + LC–MS/MS system (Sciex). Chromatography was performed on an Acquity UPLC BEH 1.7 μm; 2.1 × 100 mm column (Waters Corp., Milford, MA, USA) and analyzed by electrospray ionization mass spectrometry in the negative ion mode. A gradient program (10 mM ammonium acetate pH 9.0 as mobile phase A, acetonitrile as mobile phase B, and a flow rate of 0.400 mL/min) was used to elute TFA and the internal standard. The range of the assay was 0.020–40 ng/mL using a 25 μL aliquot of sample.
Collection of Explanted Implants and Analysis
Explanted implants were collected at the second operative visit immediately after administration of a new implant and were stored at − 20 °C or below prior to and during shipment to the bioanalytical lab.
Explanted implants were collected for measurement of any remaining travoprost and TFA. Samples were assayed in a masked manner by an independent bioanalytical laboratory (Pharmaron, Exton, PA, USA) using a validated high-performance liquid chromatography system with ultraviolet detection (HPLC–UV). Explanted implants were sonicated in the presence of tetrahydrofuran and then extracted with 1:3 acetonitrile:water. Extract aliquots (300 μL) were analyzed using an Agilent 1210 HPLC system (Agilent Technologies, Santa Clara, CA, USA) with UV detection at 277 nm. A gradient program (0.1% acetic acid in water as mobile phase A, 0.1% acetic acid in acetonitrile as mobile phase B, and a flow rate of 1.0 mL/min) was used to elute travoprost, TFA, and other travoprost-related substances. The HPLC–UV method employed a single-point calibration standard and three analytical quality control levels ranging from 0.761 to 88.7 µg/mL.
Data Analysis
All measured aqueous humor data were used in the analysis. For explanted implants, data for travoprost (prodrug) and TFA (active moiety) were summarized for analysis. Nominal sample times were used in the calculation of descriptive statistics. Concentration data below the limit of quantitation limit were defaulted to 0.00. Pharmacokinetic analysis, summarization of concentration–time data, statistical analysis, and graphical visualization of aqueous humor or implant exchange data were performed using Phoenix® WinNonlin® (version 8.4 or newer; Pharsight Corp., Mountain View, CA, USA), GraphPad Prism (version 9.5.1 or newer; Graphpad Software, San Diego, CA, USA), or Excel (Microsoft 365 version or newer; Microsoft Corp., Redmond, WA, USA). Two different lots of travoprost intracameral implants were tested in this study. Both lots met the same manufacturing specifications as those of the marketed product and data were combined for analysis and presentation purposes.
The sample size of 30 patients per cohort was considered adequate to reliably assess the aqueous humor concentration of TFA [10, 11].
Results
Demographics and Baseline Ocular Characteristics
Demographics and baseline ocular characteristics for the study population are presented in Table 2. The mean age of patients was 62.3 (range 24–85) years, there was a similar distribution of male and female patients. The study population was representative of a general population of patients with glaucoma. All patients were white, and of not Hispanic or Latino ethnicity.
Table 2
Demographics and baseline ocular characteristics
Characteristic
Overall (N = 210)
Age (years)
Mean ± standard deviation
62.3 ± 11.66
Minimum, maximum
24, 85
Age category, n (%)
18 to < 65 years
103 (49.0)
≥ 65 years
107 (51.0)
Sex,n (%)
Male
109 (51.9)
Female
101 (48.1)
Race, n (%)
White
210 (100)
Ethnicity, n (%)
Hispanic or Latino
0
Not Hispanic or Latino
210 (100)
Eye color, n (%)
Blue
7 (3.3)
Brown
166 (79.0)
Green
6 (2.9)
Hazel
31 (14.8)
Other
0
Type of disease,n (%)
Open-angle glaucoma
210 (100)
Ocular hypertension
0
Number of IOP-lowering medication classes, n (%)
0
101 (48.1)
1
48 (22.9)
2
46 (21.9)
3
15 (7.1)
IOP-lowering medication classes,n (%)
Alpha agonist
18 (8.6)
Beta blocker
80 (38.1)
Carbonic anhydrase inhibitor
59 (28.1)
Prostaglandin analog
28 (13.3)
Rho kinase inhibitor
0
Miotic
0
Intraocular pressure (mmHg)
Mean ± standard deviation
19.74 ± 4.405
Vertical cup-to-disc ratio
Mean ± standard deviation
0.68 ± 0.092
Corneal thickness (µm)
Mean ± standard deviation
539.8 ± 33.99
Shaffer angle grade,n (%)
III
55 (26.2)
IV
155 (73.8)
IOP Intraocular pressure
All patients in the study were diagnosed with OAG in the study eye. Slightly over half the patients were on one or more IOP-lowering medications at baseline, with most on a β-blocker either alone or in fixed combination with a carbonic anhydrase inhibitor or alpha agonist. Of the patients using a prostaglandin analog, all were on tafluprost (n = 28).
A total of 255 patients were screened, of whom 45 patients (17.6%) were not entered into the study due to failure to meet the inclusion criteria. Of those screened, 210 patients received an implant at the first operative visit, and a total of 195 patients (92.9%) completed the initial study period, as well as the post-exchange study period. Of the 15 patients who did not complete the study, two patients had fatal myocardial infarctions, two patients in the 24-month cohort were removed from the study due to increased IOP in the study eye necessitating filtering surgery, two were lost to follow-up, eight withdrew consent (7 of whom were in the 15-month or longer cohorts), and one moved out of the country.
Aqueous Humor Samples
Of the 195 aqueous humor samples that were collected for analysis, adequate aqueous humor sample volumes for measurement of TFA concentrations were obtained from 190 patients administered a travoprost intracameral implant. The mean ± standard deviation (SD) TFA concentrations ranged from 4.98 ± 2.50 ng/mL in samples collected 3 months post-administration to 3.35 ± 1.51 ng/mL in samples collected 24 months post-administration. At all timepoints, mean TFA levels were above the maximum aqueous humor concentration (Cmax) TFA levels (1.78 ng/mL; 3.91 ± 2.27 nM) determined after the dosing of topical travoprost ophthalmic solution, 0.004% [10], the half-maximal effective concentration, (EC50), at the FP receptor (1.60 ng/mL; 3.2 nM) [2], and the efficacious TFA level (0.1 ng/mL) estimated after intracameral dosing of a polymer-based biodegradable travoprost implant [11] (Table 3; Fig. 2).
Table 3
Descriptive statistics for travoprost free acid concentrations in the aqueous humor
Time (months)a
N
TFA aqueous humor concentrations (ng/mL)b
3
27
4.98 ± 2.50
6
25
3.74 ± 2.22
12
29
5.57 ± 3.02
15
28
2.03 ± 0.736
18
29
2.22 ± 1.24
21
27
3.80 ± 1.58
24
25
3.35 ± 1.51
TFA Travoprost free acid
aDuration from the time of administration of travoprost intracameral implant at visit 2 (first operative day 0) until the exchange procedure and collection of aqueous humor sample
bValues are the mean ± standard deviation
Fig. 2
Mean travoprost free acid (TFA) concentrations in the aqueous humor in eyes administered a travoprost intracameral implant. Error bars represent ± standard error of the mean a(as reported by Faulkner et al. [10]), b(as reported by Navratil et al. [11]). Ceff Efficacious concentration, Cmax maximum aqueous humor concentration
Residual travoprost and TFA (active moiety) concentrations were evaluated in the explanted implants from 195 patients who underwent a travoprost intracameral implant exchange procedure. Residual drug in the reservoir and cumulative release were calculated for travoprost alone, as well as for travoprost + TFA.
Residual travoprost and TFA concentrations declined in an approximately linear fashion (Table 4; Fig. 3). Cumulative percent release of travoprost and travoprost + TFA from explanted implants are presented in Table 4. A mean (± SD) of 83.7 ± 7.88% and 83.2 ± 7.95% travoprost and travoprost + TFA, respectively, remained in explanted implants 24 months post-administration. The cumulative percent travoprost + TFA release was fitted by linear regression (Fig. 4). To estimate the variability in implant elution rate, ± twofold the standard deviation of the mean values was calculated, and the resulting data were fit by linear regression. Based on these extrapolations, the expected lifetime of the travoprost intracameral implant drug elution has a mean of 29.8 months and may reach up to 36.5 months.
Table 4
In vivo release kinetics of travoprost intracameral implants
Time (months)a
N
Mean (± SD) percent (%) remaining
Mean (± SD) cumulative percent (%) release
Travoprost
Travoprost + TFAb
Travoprost
Travoprost + TFAb
3
29
78.8 ± 3.15
79.9 ± 3.31
21.2 ± 3.15
20.1 ± 3.31
6
28
69.8 ± 8.51
72.1 ± 4.62
30.2 ± 8.51
27.9 ± 4.62
12
29
50.2 ± 6.58
52.0 ± 6.84
49.8 ± 6.58
48.0 ± 6.84
15
28
38.6 ± 8.23
41.6 ± 5.08
61.4 ± 8.23
58.4 ± 5.08
18
29
34.8 ± 7.09
35.6 ± 7.52
65.2 ± 7.09
64.4 ± 7.52
21
27
28.0 ± 5.76
28.6 ± 5.90
72.0 ± 5.76
71.4 ± 5.90
24
25
16.3 ± 7.88
16.8 ± 7.95
83.7 ± 7.88
83.2 ± 7.95
SD Standard deviation, TFA travoprost free acid
aDuration from the time of administration of travoprost intracameral implant at visit 2 (first operative day 0) until the exchange procedure and collection of aqueous humor sample
bData represent a summation of travoprost (prodrug) and TFA (active metabolite) percent release
Fig. 3
Mean percent (%) remaining travoprost + travoprost free acid (TFA) in explanted implants removed from eyes administered travoprost intracameral implants. Data represent a summation of travoprost (prodrug) and TFA (active metabolite). Error bars represent ± standard error of the mean
Cumulative travoprost + travoprost free acid (TFA) percent (%) release from explanted implants removed from eyes administered travoprost intracameral implants. Data represent a summation of travoprost (prodrug) and TFA (active metabolite) and were analyzed by linear regression. Dotted lines represent linear regression lines fitted to ± 2 standard deviations (SD) of the mean data. Green dots are extrapolations of the mean data
Prior to the initial administration of the travoprost intracameral implant, patients had a baseline mean (± SD) IOP of 19.7 ± 4.41 mmHg in their study eye, with 48.1% of patients on no IOP-lowering medication and the remaining 51.9% on one to three medications. Mean (± SD) number of IOP-lowering medications per study eye was 0.88 ± 0.99 at baseline (Fig. 5). At the pre-exchange visit conducted within 10 days prior to the second operative visit and which ranged from 3 to 24 months after the first operative visit, mean IOP was 15.8 ± 3.20 mmHg with patients on a mean of 0.05 ± 0.23 topical IOP-lowering medications.
Fig. 5
Mean intraocular pressure (IOP) in study eyes and number of concomitant IOP-lowering medications (# IOP Meds) taken by patients administered travoprost intracameral implants. n Value under the IOP represents the number of patients at each visit following their initial administration of a travoprost intracameral implant, and varies depending on the cohort to which patients were assigned
Through month 24, IOP remained relatively stable, with few patients on additional IOP-lowering therapy. At the pre-exchange visit, which varied in duration post-administration dependent on the cohort, mean (± SD) IOP was 15.8 ± 3.20 mmHg in the 195 patients undergoing exchange.
Not unexpectedly, the mean number of concomitant medications was highest in the 24-month cohort in which three of the 25 patients (12%) were on one or more concomitant IOP-lowering medications at their pre-exchange visit. Furthermore, two patients in this cohort were discontinued from study prior to their month 24 visit due to elevated IOP requiring trabeculectomy surgery.
Adverse Events
A summary of treatment-emergent adverse events is presented in Table 5. There were no serious/sight-threatening adverse events in the study eye, nor any severe adverse events in the study eye. There were no observations of iris color change in any study eye. Two patients in the 24-month cohort were discontinued from study due to adverse events of increased IOP. Two treatment-related intraoperative adverse events (iridodialysis and hyphema) were reported in single patients each.
Table 5
Summary of treatment-emergent adverse events
Adverse events
Overall (N = 210)a, n (%)
Overall adverse events
17 (8.1)
Study eye
8 (3.8)a
Non-ocular or non-study eye
10 (4.8)b
Treatment-related adverse events
2 (1.0)
Study eye
2 (1.0)c
Non-ocular or non-study eye
0
Maximum severity—study eye
Mild
5 (2.4)
Moderate
3 (1.4)
Severe
0
Maximum severity—non-ocular or non-study eye
Mild
7 (3.3)
Moderate
1 (0.5)
Severe
2 (1.0)d
Adverse events resulting in study discontinuation
2 (1.0)
Study eye
2 (1.0)e
Non-ocular or non-study eye
0
Serious adverse events
2 (1.0)
Study eye
0
Non-ocular or non-study eye
2 (1.0)d
Deaths
2 (1.0)d
aStudy eye adverse events included iridodialysis (1 patient on the day following the exchange procedure), hyphema (1 patient on the day following the initial administration), and increased intraocular pressure (5 patients during the initial study period, 1 patient during both the initial and post-exchange follow-up, and 1 patient during the post-exchange follow up)
bNon-ocular adverse events included myocardial infarction (2 patients), corona virus infection (5 patients), influenza (2 patients), and pneumonia (1 patient). There were no adverse events in the non-study eye
cTreatment-related adverse events in the study eye included iridodialysis and hyphema
dTwo patients experienced serious fatal severe adverse events of myocardial infarction
eTwo patients in the 24-month cohort experienced increased intraocular pressure at study day 493 and study day 495, resulting in study discontinuation
Discussion
In this study, the ocular pharmacokinetics of the travoprost intracameral implant 75 µg was studied over a period of 24 months in 210 patients with OAG. The study demonstrated that the implant provided consistent delivery of travoprost to the anterior chamber of the eye and maintained aqueous humor TFA concentrations above estimated efficacious levels for at least 24 months. This was corroborated by the well-controlled IOP levels maintained throughout the 24-month period and the low number of concomitant IOP-lowering medications.
The mechanism of action for prostaglandin analogs in lowering IOP is hypothesized to occur through activation of the FP receptors in the ciliary body, sclera, and trabecular meshwork [2‐7]. However, for practical and ethical reasons, travoprost concentrations in these tissues cannot be measured in humans. Aqueous humor, however, may be sampled with low risk to the patient and is frequently used as a surrogate for understanding drug concentrations within ocular tissues. TFA concentrations in the aqueous humor following topical or intracameral administration of travoprost to patients have been reported by others and provide an estimation of the concentrations needed to maintain efficacy. In one study, following once-daily topical administration of TRAVATAN® (travoprost ophthalmic solution, 0.004%) for at least 21 days to patients with OAG or OHT, the maximum aqueous humor TFA concentration (Cmax) was 1.78 ng/mL (3.91 ± 2.27 nM) [10]. These levels of aqueous humor have been reported to lower IOP by 7–8 mmHg from an unmedicated baseline of 26 mmHg [12‐15]. In another study, travoprost was administered to patients via an intracameral polymer-based biodegradable implant (ENV515 intracameral travoprost XR; Envisia Therapeutics, Durham, NC, USA) delivered to the anterior chamber [11]. The authors reported that aqueous humor TFA concentrations of 0.1 ng/mL achieved a reduction in IOP of 6.7 ± 3.7 mmHg (25% lowering) over 11 months. In the current study, continuous travoprost elution from the implant resulted in steady-state TFA concentrations ranging from 4.98 ± 2.50 ng/mL at 3 months to 3.35 ± 1.51 ng/mL at 24 months. Although aqueous humor concentrations declined slightly at 15 and 18 months, this was not associated with a lessening in IOP-lowering efficacy, and all individual patient samples at all timepoints had TFA concentrations that were above the value (0.1 ng/mL) established by Navratil et al. [11] as efficacious in lowering IOP, with the vast majority above the Cmax for topical administration of travoprost reported by Faulkner et al. [10] and the EC50 (1.60 ng/mL; 3.2 nM) at the FP receptor. Consistent with the observation that the TFA concentrations in the current study were above the minimally efficacious concentration established by Navratil et al. [11] and above those observed following topical administration of travoprost, we note that the travoprost intracameral implant has demonstrated robust IOP-lowering efficacy, and excellent safety and tolerability through 3 years [9].
The administration of topical PGAs results in large fluctuations of PGA concentrations in the eye due to the bolus nature of administration and rapid elimination mechanisms [10, 16‐18]. Moreover, patients are poorly adherent to topical PGA therapy, potentially due to a combination of their side effects and impact on quality of life, as well as the initially asymptomatic, silent nature of the disease [19‐23]. The travoprost intracameral implant was designed to continually elute travoprost in a gradual fashion over time, thus eliminating the peaks and troughs in travoprost concentrations seen with topical therapy. In this study, explanted implants from patients treated with the travoprost intracameral implant were examined for residual travoprost and TFA concentrations to establish an understanding of the intraocular release kinetics of the implant. An average of 48.0 ± 6.84% and 83.2 ± 7.95% of travoprost and TFA was released from the implant at 12 and 24 months post-administration, respectively. Linear regression analysis of the cumulative release data resulted in good fit (R2 = 0.9953), indicating a zero-order release of the drug from the implant from 3 to 24 months and demonstrating the ability of the implant to deliver consistent travoprost concentrations into the anterior chamber. This continuous drug elution rate is also reflected in the steady-state TFA drug levels in the aqueous humor that were maintained throughout the study period. Extrapolation of the mean data beyond 24 months showed a mean duration of travoprost release of 29.8 months. To take into account variability within drug release, sampling techniques, and the analytical method, we calculated the regression of ± 2 SD of the mean, and the duration of implant release was again estimated. Based on these extrapolations, the expected lifetime drug elution of the travoprost intracameral implant ranges up to 36.5 months. These estimates are in agreement with the duration of IOP-lowering efficacy observed in this study (up to 24 months), and also in a phase 2 trial in which travoprost intracameral implant provided robust IOP-lowering and substantially reduced topical IOP-lowering medication burden for up to 36 months [9].
The safety of the implants and exchange procedure was favorable. No sight-threatening or severe study eye adverse events reported in the trial, and intracameral implants were exchanged successfully in 195 patients.
This study is not without its limitations. Sparse sampling in which a single sample was obtained from each patient, instead of serial sampling in which multiple samples would be collected from each patient, was used to determine aqueous humor and implant travoprost and TFA concentrations. This is a common limitation for ocular pharmacokinetic studies in human patients in which intraocular sampling is invasive and serial sampling is impractical. However, in this study, we were able to obtain aqueous humor samples and explanted implants from up to 29 patients per timepoint, which aided in reducing the variability often seen with sparse sampling techniques.
In addition, the study was not designed to evaluate IOP because there were no IOP entry criteria and those patients on IOP-lowering medications (51.9% of the total patient population) were not required to undergo a washout period. Moreover, IOP measurements at each visit were not collected at a prespecified time of day and therefore were potentially impacted by diurnal IOP fluctuation. However, the study provides real-world data on IOP-lowering in patients administered a travoprost intracameral implant and the ensuing reduction in topical IOP-lowering medication burden.
Finally, there was a lack of racial diversity in our study. However, we believe that the pharmacokinetic results are applicable to different patient populations since a prior study has shown no difference in prostaglandin analog IOP-lowering efficacy between white and non-white patients [24].
Conclusions
Travoprost intracameral implant provided consistent delivery of travoprost to the anterior chamber of the eye and maintained TFA concentrations in the aqueous humor at above estimated efficacious levels for at least 24 months. This was corroborated by the level of IOP control and low number of concomitant IOP-lowering medications over the 24-month evaluation period. Furthermore, travoprost intracameral implant had 16% of its payload remaining at 24 months, thus explaining the travoprost intracameral implant’s robust IOP-lowering efficacy observed through 3 years [9].
Medical Writing, Editorial, and Other Assistance
The authors acknowledge Teresa P. Mena for managing the clinical trial; Debbie S Capel, Samuel Placinta, Rachel J Wilson, and Danielle N Armijo for their assistance with trial logistics; Iona D Raymond, Jia-Ying Yang, and Inhou Chu for oversight of bioanalytical testing; and Sara Heedy for assistance with the preparation of figures for this manuscript.
Authorship
Authorship of this manuscript is in accordance with the guidelines of the International Committee of Medical Journal Editors.
Declarations
Conflict of Interest
Gabriella Szekely, Kerry G Stephens, Long V Doan, Jennifer R Seal, Todd Fjield, David Applegate, Dale W Usner, L Jay Katz, Angela C Kothe, and Tomas Navratil are employees of Glaukos and may hold open stock and/or stock options. Lilit A Voskanyan received research funding from Glaukos Corporation for the conduct of the study. Mohammed E ElMallah has received research funding from Glaukos Corporation and New World Medical.
Ethical Approval
The study was performed in accordance with International Council on Harmonisation good clinical practices, the tenets of the Declaration of Helsinki, and regulations governing clinical trials in Armenia, and with approval of the relevant institutional review board/independent ethics committee (Ethics Committee of Ophthalmological Center named after S.V. Malayan, Yerevan, Armenia 0048; approval date: 21 December 2019). Written informed consent was obtained from all patients prior to undertaking any study-related procedures.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Aqueous Humor Concentrations of Travoprost Free Acid and Residual Drug in Explanted Implants from Patients Administered a Travoprost Intracameral Implant
Verfasst von
Gabriella Szekely
Lilit A. Voskanyan
Kerry G. Stephens
Long V. Doan
Jennifer R. Seal
Mohammed K. ElMallah
Todd Fjield
David Applegate
Dale W. Usner
L. Jay Katz
Angela C. Kothe
Tomas Navratil
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