Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma

Abstract

Purpose:

To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad^® (TRAVATAN^®) in pediatric patients with glaucoma or ocular hypertension.

Methods:

This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (C_max).

Results:

Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean C_max was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs.

Conclusions:

Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and C_max. No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.

Introduction

Glaucoma is a progressive optic neuropathy that can be caused by multiple medical conditions in children, including congenital diseases, and can lead to blindness.¹ Elevated intraocular pressure (IOP) is a leading risk factor for the development of glaucoma, and IOP reduction is the only known means of slowing or halting disease progression.² Pediatric glaucoma is diagnosed in patients <18 years based on a combination of factors, including elevated IOP, optic disc cupping, Haab striae, progressive myopia coupled with an increase in ocular dimensions, and visual field defects.³ Primary childhood glaucomas are attributable to developmental and congenital abnormalities that affect outflow mechanisms.¹ In pediatric patients, glaucoma is managed mainly through surgical interventions.¹ However, medical therapy to control elevated IOP plays a significant supportive role in the management of pediatric glaucoma¹ and can provide a long-term treatment approach following surgical procedures.

Travoprost 0.004% (40 μg/mL; TRAVATAN^®; Alcon Laboratories, Inc., Fort Worth, TX) preserved with Polyquad^® (a polymeric quaternary ammonium preservative with cationic antimicrobial properties that is an alternative to benzalkonium chloride, a preservative associated with cytotoxic effects and symptoms of ocular surface damage^4,5) is currently approved for the reduction of elevated IOP in adults with primary open-angle glaucoma or ocular hypertension.

To date, only retrospective studies provide evidence of the effectiveness and safety of travoprost 0.004% in pediatric patients with glaucoma or ocular hypertension. A retrospective medical record review of 57 pediatric patients with glaucoma by Yanovitch et al. (mean age, 7 years) demonstrated that once-daily travoprost 0.004% reduced IOP by 4.2–6.3 mmHg from a baseline of 26.3 mmHg after 1 month to 1.5 years of treatment.⁶ The most frequent adverse events (AEs) were eyelash thickening and elongation, conjunctival injection, and ocular irritation. A study of travoprost as an adjunct treatment in pediatric patients diagnosed with glaucoma (mean age 7.6 years) also showed a travoprost-dependent reduction in IOP after 18–48 months of treatment. The mean IOP reduction after the addition of travoprost was 5.3 mmHg from a mean baseline of 26.7 mmHg. AEs included conjunctival redness, irritation, sleep disturbance, increased eyelash length and thickness, and pigmentation.⁷

The systemic pharmacokinetics (PKs) of travoprost has been studied in adult populations, including patients with glaucoma.⁸ Following topical ocular administration, travoprost undergoes rapid and complete hydrolysis to the pharmacologically active free acid. Systemic absorption of topical ophthalmic medications, such as travoprost, can occur while passing through the lacrimal drainage system.¹ Once in the systemic circulation, travoprost free acid undergoes subsequent metabolism via β-oxidation. Plasma travoprost free acid concentrations in adults are low, generally below the 0.010 ng/mL assay limit of quantitation in most cases.⁸ Pediatric patients have lower body mass and body surface area (BSA), lower renal clearance, and smaller blood volume, potentially resulting in higher circulating concentration of medications, an increase in elimination half-life, and a higher risk of systemic AEs.^1,9,10

The purpose of this study was to assess the steady-state plasma PK and the safety of travoprost 0.004% preserved with Polyquad in pediatric patients with glaucoma or ocular hypertension. The results of this study will provide additional PK and physiologic data for establishing a safe dosage of travoprost in pediatric patients.

Methods

Study design

This was a 7-day, multicenter, open-label phase 1 study conducted at 7 investigational centers located in the United States, Saudi Arabia, France, and Spain between January and July 2013 (ClinicalTrials.gov identifier NCT01658839).

This study was designed to enroll ∼24 patients, with at least 3 patients in each of the following age subgroups: 2 months to <3 years; 3 to <12 years; and 12 to <18 years. No statistical power calculations were conducted relative to the determination of this sample size. The sample size was empirical and consistent with conventions for PK studies. The study consisted of a screening visit (day −21 to day 0) and 2 on-therapy visits conducted at day 1 and day 7. Postscreening, patients discontinued any prescribed topical prostaglandin analogs. At the day 1 visit, patients received their first dose of travoprost 0.004% preserved with Polyquad at the investigational center; the patients (or their parents/guardians) were instructed to instill 1 drop of travoprost into each eye once daily at 9 am (±60 min) on day 2 and all subsequent days for at least 7 days (range 7–12 days). At the day 7 visit, patients received travoprost 0.004% preserved with Polyquad at the investigational center.

The study was approved by all institutional review boards and was conducted in accordance with Good Clinical Practice and in compliance with the ethical principles of the Declaration of Helsinki, and, for sites in the United States, conformed to the requirements of the Health Insurance Portability and Accountability Act. Written informed consent was provided by patients' parents or guardians and assent was obtained based on patient age.

Patients

Eligible patients were aged ≥2 months to <18 years and diagnosed with glaucoma or ocular hypertension in at least 1 eye. Patients with conditions requiring chronic treatments with glucocorticoids that resulted in steroid-induced glaucoma were also included in the study. Key exclusion criteria were chronic, recurrent, or severe inflammatory eye disease; ocular trauma requiring medical attention ≤3 months before screening; ocular infection or inflammation or intraocular surgery ≤30 days before screening; clinically significant or progressive retinal disease; lack of a stable dosing regimen of any medications for ≥30 days before screening; body weight <5 kg; or only 1 sighted eye or unable to receive travoprost in both eyes for any reason.

Pharmacokinetics

Plasma samples were collected within 30 min before the final dose of travoprost 0.004% preserved with Polyquad, and at 10, 20, 40, and 80 min postdose. BSA was calculated using the Mosteller algorithm, in which BSA (cm²) = the square root of (height in cm × weight in kg)/3600. All data were summarized with descriptive statistics. Patients who received ≥2 doses of travoprost 0.004% preserved with Polyquad and had ≥1 postdose blood draw were included in the analysis.

Travoprost free acid plasma concentrations were determined using a high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) method using solid phase extraction. The method has a lower limit of quantitation (LLOQ) of 0.010 ng/mL.

PK parameters evaluated in patients were the maximum analyte plasma concentration (C_max), time to reach C_max (T_max), time to last measurable concentration (T_last), area under the plasma concentration-time curve to the last quantifiable sampling time point (AUC_0–last), area under the plasma concentration-time curve extrapolated to infinity (AUC_0–∞), and elimination half-life in plasma (t_1/2).

Safety

Safety was evaluated based on AEs, IOP, best corrected visual acuity, vital signs, and alertness assessments. Clinically significant findings from these assessments were reported as AEs. A standard digital 12-lead electrocardiogram (ECG) was recorded at screening, day 7, or early exit; measurement was performed with the patient in a supine position. Vital signs (temperature, respiration, pulse, and blood pressure) were measured at screening, day 1, and day 7 or early exit. Alertness was assessed at day 1 (predose) and day 7 (postdose) or early exit, according to the grading scales for responsiveness (graded 1–5, deep sleep to alert), speech (graded 2–5, few recognizable words to normal speech), facial expression (graded 3–5, marked relaxation to normal), and eyes (graded 3–5, glazed and marked ptosis to clear and no ptosis). Best-corrected visual acuity testing was performed at screening and day 7 or early exit, before IOP measurements. The screening visit test was used consistently for the remainder of the study.

Preverbal children were evaluated based on “fixation and following” behavior, using a toy or the examiner's face (for children <6 months old). Verbal children were evaluated by either a “Tumbling E” chart, picture optotypes (ie, Allen cards or equivalent), the HOTV test, or Snellen letter or number charts.

Slit-lamp biomicroscopy was used to evaluate the cornea, iris, anterior chamber, lens, eyelids, and conjunctiva in both eyes at screening and day 7 or early exit. The examinations were conducted before the IOP measurements. Ocular hyperemia was evaluated at day 1 and day 7 or early exit by gross visual inspection and graded 0 (none) to 3 (severe). Dilated fundus examination of both eyes was performed at screening, day 1, and day 7 or early exit and graded using scales for vitreous (0 or 1), retina/macular/choroid inflammation (0–2, normal to active inflammation), and optic nerve (0–3, normal to severe damage). IOP was measured in both eyes at every visit using a calibrated tonometer and a combination of an anesthetic and coloring agent. Two consecutive IOP measurements were taken for each eye at every assessment.

Statistical analysis

PK parameters were evaluated using the PK analysis set, which included all patients who received ≥2 doses of the study drug, satisfied protocol-required criteria, had ≥1 postdose blood draw, and had adequate PK data collected. Descriptive statistics were generated for each of the PK parameters. AUC_0–last and AUC_0–∞ were estimated using noncompartmental analysis methods. t_1/2 was calculated as ln(2)/λ, where λ is the elimination rate constant.

The safety population included all patients who received the study drug. All reported AEs were coded using the Medical Dictionary for Regulatory Activities and were presented by severity. The extent of exposure was calculated as days on therapy.

Results

Demographics

Twenty-five patients received travoprost 0.004% preserved with Polyquad and were included in the safety population. One patient was excluded from the PK analysis set (n = 24) because the collected samples were lost due to a centrifuge malfunction at the site. The mean ± standard deviation (SD) age of the remaining 24 patients is 9.6 ± 4.9 years (range 0.3–17 years); 12 patients (50%) were female; and 12 patients were white, 11 were black or African American, and 1 was multiracial.

PK analysis

Eleven patients had ≥1 sample with quantifiable travoprost free acid concentrations (0.010–0.0545 ng/mL); concentrations were quantifiable in 19 of 119 plasma samples. Individual PK parameters for these 11 patients are presented in Table 1. In 24 patients, predose concentrations of travoprost, measured before the administration of the final dose on day 7, were below the level of detection (<0.01 ng/mL). Samples from 1 patient were lost due to a centrifuge malfunction. These results demonstrate that there was no accumulation of the travoprost free acid in plasma over the course of the treatment.

Table 1.

Pharmacokinetic Parameters for Pediatric Patients with Quantifiable Travoprost Free Acid Plasma Concentrations

Patient	Age (years)	BSA (m²)	C_max (ng/mL)	T_max (h)	T_last (h)	AUC_0–last (ng·h/mL)	AUC_0–∞ (ng·h/mL)	t_1/2 (h)
1	8	1.049	0.0165	0.17	0.17	NC	NC	NC
2	7	0.902	0.0256	0.17	0.33	0.00595	NC	NC
3	6	0.822	0.0226	0.17	0.33	0.00475	NC	NC
4	1^a	0.483	0.0396	0.18	0.33	0.00908	NC	NC
5	12	1.314	0.0105	0.67	0.67	NC	NC	NC
6	12	1.656	0.0108	0.33	0.33	NC	NC	NC
7	6	0.837	0.0486	0.17	1.33	0.0313	0.0389	0.53
8	10	1.302	0.0297	0.18	0.33	0.00737	NC	NC
9	<1^b	0.366	0.0545	0.33	0.33	0.0111	NC	NC
10	15	1.682	0.0114	0.17	0.17	NC	NC	NC
11	10	1.088	0.0120	0.17	0.17	NC	NC	NC

15 months.

3 months.

AUC_0–∞, area under the plasma concentration-time curve extrapolated to infinity; AUC_0–last, area under the plasma concentration-time curve to the last quantifiable sampling time point; BSA, body surface area; C_max, maximum analyte plasma concentration; NC, not calculated due to insufficient data; t_1/2, elimination half-life in plasma; T_last, time to last measureable concentration; T_max, time to reach C_max.

Maximum concentration, T_max, and T_last were calculated for patients with ≥1 quantifiable travoprost free acid concentration. Overall mean ± SD travoprost C_max is 0.0256 ± 0.0158 ng/mL. Patients aged 2 months to <3 years had a mean C_max of 0.0471 ± 0.0105 ng/mL, patients aged 3 to <12 years had a mean C_max of 0.0258 ± 0.0128 ng/mL, and patients aged 12 to <18 years had a mean C_max of 0.0109 ± 0.0005 ng/mL. The highest concentration of travoprost (0.0545 ng/mL) was observed in the patient with the lowest BSA (0.366 m²). However, there was no clear relationship between age/BSA and travoprost exposure, as the other 2 patients in this age group had no quantifiable plasma concentrations of travoprost.

The overall mean ± SD travoprost T_max is 15.0 ± 9.0 min and T_last is 25.2 ± 21.0 min. The mean T_max and T_last values for patients aged 2 months to <3 years were 15.6 ± 6.6 and 20.4 ± 0.6 min, respectively. The mean T_max and T_last values for patients aged 3 to <12 years were 10.2 ± 0.0 and 27.6 ± 28.2 min, respectively. Both the mean T_max and T_last values for patients aged 12 to <18 years were 23.4 ± 15.6 min.

Nine patients aged 6 to 15 years had ≥1 quantifiable travoprost free acid concentration, with 1 patient having quantifiable travoprost free acid concentrations at all postdose collection time points. The mean AUC_0–last was 0.0166 ± 0.0099 ng·h/mL. Both t_1/2 and AUC_0–∞ were evaluated in 1 patient (aged 6 years): t_1/2 was 31.8 min and AUC_0–∞ was 0.0389 ng·h/mL.

Safety

The mean ± SD duration of exposure to travoprost is 8.4 ± 1.4 days (range 7–12 days). No patients died during the study. One serious AE was reported for a patient who was scheduled for an overnight hospitalization before trabeculectomy surgery (Table 2). The planned trabeculectomy surgery was reported by the investigator as not related to the use of travoprost 0.004% preserved with Polyquad, and the patient was not discontinued from the study. Three treatment-related AEs were reported (Table 2): ocular hyperemia, eye pain, and eye pruritus (n = 1 each). There were no meaningful changes in vital signs (pulse, systolic and diastolic blood pressure, respiration, and body temperature), alertness, visual acuity, slit-lamp examination, or fundus parameters in any of the patients.

Table 2.

Summary of Treatment-Emergent Adverse Events

	Travoprost 0.004% preserved with Polyquad (n = 25)
AE category	n	%
Deaths	0	0
Serious AEs	1^a	4
Patients discontinued because of an AE	0	0
Patients with ≥1 treatment-emergent AE	5	20
Treatment-emergent AEs
Ocular hyperemia	1	4
Eye pain	1	4
Eye pruritus	1	4
Conjunctival hemorrhage	1	4
Ear pain	1	4
Trabeculectomy^a	1	4
Treatment-related AEs
Ocular hyperemia	1	4
Eye pain	1	4
Eye pruritus	1	4

Scheduled overnight hospitalization for trabeculectomy surgery; not related to treatment.

AE, adverse event.

In 6 patients, a shift to abnormal ECG was observed from baseline to day 7 or exit visit. The abnormal ECGs were explained by prolonged QTc (n = 4) or intraventricular conduction defect (n = 4). In 4 of these patients, the levels of travoprost free acid were below the level of detection (<0.01 ng/mL). In 2 patients with abnormal ECG (aged 3 months and 7 years), there were quantifiable amounts of travoprost free acid. Changes in patients' ECGs were concluded to be not clinically significant by clinicians. No AEs associated with an abnormal ECG were reported.

Mean hyperemia scores were numerically greater at day 7 or exit visit compared with day 1 for patients ≥3 years old. As expected with travoprost 0.004% preserved with Polyquad, there was a numerical decrease in IOP in pediatric patients from baseline to day 7 or exit visit.

Discussion

Comparison of travoprost pediatric exposure data with previous Alcon studies conducted in adult populations showed similar PK across age groups. These studies included healthy adults, adults with renal impairment, adults with hepatic impairment, and healthy adult Japanese volunteers (Alcon, unpublished data). Similar to the results reported in this study for pediatric patients, the systemic exposure to travoprost free acid in adults was low and showed variability. Of 107 participants across the 4 adult PK studies, 68 had travoprost free acid concentrations below the limit of quantitation (<0.010 ng/mL) at all time points. For the remaining 39 participants, travoprost concentrations ranged from below the limit of quantitation to 0.0520 ng/mL. In the current pediatric study, the concentration of travoprost free acid was observed to range from below the limit of quantitation to 0.0545 ng/mL. These data suggest that the range of systemic drug exposure across the pediatric population was comparable to that observed across the 4 adult populations.

The systemic PKs of the structurally similar prostaglandin analog latanoprost in pediatric and adult patients has been previously reported.¹¹ In the latanoprost study, plasma exposure to latanoprost acid was markedly higher in the youngest age cohort (0 to <3 years) compared with older children and adults. Median plasma latanoprost acid concentrations at the earliest collection time point (5 min) were ∼0.160 ng/mL in the 0- to 3-year cohort compared with ∼0.030 and <0.020 ng/mL in 3- to <12-year-olds and adults ≥18 years, respectively, at 5 min. The higher exposure in the youngest age group in the latanoprost study was apparently not due to longer half-life, but instead may have reflected the smaller volume of distribution in this population. Travoprost and latanoprost undergo similar metabolic pathways of hydrolysis of the ester moiety, followed by stepwise β-oxidation of the active free acids. The reason for the lack of higher exposure to travoprost acid in the youngest patients is unclear, in contrast to the trend observed with latanoprost, and despite the structural similarity and identical clearance mechanisms between the 2 compounds.

There were 6 patients who experienced a shift to abnormal ECG. The changes in ECGs were not considered to be clinically significant, and there were no reports of AEs associated with abnormal ECGs. Four of the 6 patients did not have detectable blood levels of travoprost free acid; of the 12 patients with detectable levels of the travoprost free acid, 2 experienced a shift to abnormal ECG. Previous studies did not reveal any cardiac concerns associated with the use of topical prostaglandin analogs in pediatric patients.^6,11–13

Our study, though limited by a small number of patients, showed that plasma concentrations of travoprost free acid were below the LLOQ of the assay in the majority of patient blood samples, and exposure was low in patients with measurable samples. No clear associations were observed between age/BSA and PK parameters. A similar study of latanoprost did observe higher systemic exposure (C_max) in pediatric patients with glaucoma,⁵ which was attributed to lower body weight in the younger patients. Findings from the current study also revealed higher C_max in younger patients; however, the numbers in each group were too small to draw meaningful conclusions. The high variability of C_max and other PK parameters in pediatric patients, especially in newborns, has been previously described and makes data interpretation challenging.⁹ The limited range of systemic exposure in children was similar to exposure data reported for adults treated with travoprost.⁸

Based on the low incidence of AEs and measured safety parameters, no increased risk for the use of travoprost 0.004% preserved with Polyquad in pediatric patients <18 years of age, including patients younger than 3 years, was identified relative to the known risks of travoprost 0.004%.

Footnotes

Acknowledgments

Medical writing assistance was provided by Natalia Zhukovskaya, PhD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA), and was funded by Alcon.

Author Disclosure Statement

This study was funded by Alcon Laboratories, Inc., Fort Worth, TX. Alcon participated in the design and conduct of the study, data collection, data management, data analysis, and preparation of this manuscript. E.S. received research funding from Alcon, Omeros, Ophtec, and Retrophin. T.L., M.C., and K.G. are Alcon employees. D.B.-G., S.A.S., and E.R.D. have no conflicts of interest to disclose. This study was sponsored by Alcon Research, Ltd. (Fort Worth, TX).

References

Moore

, and Nischal

K.K.

Pharmacologic management of glaucoma in childhood. Paediatr. Drugs., 9:71–79, 2007.

Sultan

M.B.

, Mansberger

S.L.

, and Lee

P.P.

Understanding the importance of IOP variables in glaucoma: a systematic review. Surv. Ophthalmol., 54:643–662, 2009.

Freedman

, Beck

, Levin

, and Walton

Sticky situations in pediatric glaucoma and what they taught us—lessons learned the hard way. Presented at: 39th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus: April 3–7, 2013; Boston, MA.

Brignole-Baudouin

, Riancho

, Liang

, and Baudouin

Comparative in vitro toxicology study of travoprost polyquad-preserved, travoprost BAK-preserved, and latanoprost BAK-preserved ophthalmic solutions on human conjunctival epithelial cells. Curr. Eye Res., 36:979–988, 2011.

Pisella

P.J.

, Pouliquen

, and Baudouin

Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br. J. Ophthalmol., 86:418–423, 2002.

Yanovitch

T.L.

, Enyedi

L.B.

, Schotthoeffer

E.O.

, and Freedman

S.F.

Travoprost in children: adverse effects and intraocular pressure response. J. AAPOS., 13:91–93, 2009.

Helmanová

, Autrata

, Šenková

, and Řehůřek

Safety and efficacy of travoprost adjunctive treatment in paediatric glaucoma. Scripta Medica (BRNO). 80:29–36, 2007.

McCue

B.A.

, Cason

M.M.

, Curtis

M.A.

, Faulkner

R.D.

, and Dahlin

D.C.

Determination of travoprost and travoprost free acid in human plasma by electrospray HPLC/MS/MS. J. Pharm. Biomed. Anal., 28:199–208, 2002.

Bartelink

I.H.

, Rademaker

C.M.

, Schobben

A.F.

, and van den Anker

J.N.

Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin. Pharmacokinet., 45:1077–1097, 2006.

10.

Coppens

, Stalmans

, Zeyen

, and Casteels

The safety and efficacy of glaucoma medication in the pediatric population. J. Pediatr. Ophthalmol. Strabismus., 46:12–18, 2009.

11.

Raber

, Courtney

, Maeda-Chubachi

, et al. Latanoprost systemic exposure in pediatric and adult patients with glaucoma: a phase 1, open-label study. Ophthalmology. 118:2022–2027, 2011.

12.

Black

A.C.

, Jones

, Yanovitch

T.L.

, et al. Latanoprost in pediatric glaucoma—pediatric exposure over a decade. J. AAPOS., 13:558–562, 2009.

13.

Maeda-Chubachi

, Chi-Burris

, Simons

B.D.

, et al. Comparison of latanoprost and timolol in pediatric glaucoma: a phase 3, 12-week, randomized, double-masked multicenter study. Ophthalmology. 118:2014–2021, 2011.