Purchase this article with an account.
Alan Laties, Randall Stoltz, Chaim Brickman, Vernon Humbert, N. Slomowitz, William McVicar, Rudolf Baumgartner; A Randomized, Phase I Dose-Escalation Study to Evaluate Tolerability, Safety and Pharmacokinetics (PK) of Trabodenoson in Healthy Older-Adult Volunteers. Invest. Ophthalmol. Vis. Sci. 2013;54(15):458.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The safety, tolerability and PK of trabodenoson eye drops, a highly-selective adenosine-1 agonist, were assessed in healthy adult subjects.
In a Phase I unit, eligible adults after informed consent entered 1 of 7 sequential 10-subject cohorts (6 trabodenoson: 4 placebo). Cohorts 1-6 (Part 1) received monocular treatment with placebo or 200-3200 μg of trabodenoson BID for 14 days. Cohort 7 (Part 2) received step-wise escalating binocular doses of trabodenoson, from 1800-6400 μg total body dose. A single escalating dose (no punctual occlusion) was applied every 48 hrs to decrease the potential for systemic tolerance.
70 subjects (35-65 yrs) were randomized to placebo (n=28) or trabodenoson (n=42). The highest achievable dose (3200 µg per eye) was reached; no MTD was identified. No severe or study-drug-related serious AEs, or dose-limiting toxicities were reported. Systemic: Cardiovascular evaluations (heart rate, blood pressure, ECG, Holter and telemetry monitoring) showed no effect at any dose or time point. Troponin levels were normal in all subjects except for a transient elevation in one placebo subject. Pulmonary, CNS, and renal measurements showed no treatment-related effects. Ocular: Serial BCVA, IOP, and complete eye examinations elicited no safety signal. Ocular AEs, in Cohorts 1-6, were uncommon, self-limited, and usually mild with similar incidence for placebo (n=4; 14%) and active (n=6; 14%). Ocular hyperemia was reported in Part 1 in one subject (2.8%) (200μg dose, moderate, duration 1 hour and self-limited) and none in Part 2. In Part 2 there was one ocular AE - photophobia, reported in the placebo group. In Part 1, a small dose-dependent reduction in IOP was detected in several Cohorts (baseline IOP ~13 mmHg). PK: exposure to trabodenoson was dose-related with a plateau effect at the highest doses (at the 3 highest doses in Part 2, there was no increase in exposure with increasing dose). Median Tmax was 0.08 to 0.27 hrs and the mean t1/2 0.48 to 2.0 hrs across all doses. Drug did not accumulate in plasma following repeated administration.
Trabodenoson, up to the highest pragmatic achievable dose, was safe and well-tolerated. No MTD was identified. Trabodenoson had a short t1/2, no accumulation after repeated dosing, and limited systemic exposure.
This PDF is available to Subscribers Only