A Novel Study Using Accelerated Mass Spectrometry to Evaluate the Pharmacokinetics of Total (14)C AL-8309 (Tandospirone) Following Topical Ocular Administration in Healthy Male Subjects

The primary objective of this study is to characterize the pharmacokinetics of total (14)C concentrations following bilateral, topical ocular drops of (14)C-AL-8309B labeled either at the pyrimidyl ring (cohort A) position or at the imido-carbonyl ring (cohort B) position twice daily from day 1 through day 6 and once in the morning of day 7 in 16 healthy male subjects (8 per cohort). Each drop (approximately 24 μL) of (14)C-AL-8309B 1.75% ophthalmic solution (equivalent to 420 μg-equiv AL-8309) contained approximately 500 nCi of (14)C-AL-8309. AL-8309 systemic absorption was relatively slow; the time of maximum observed plasma concentrations ranged from 0.25 to 3 hours. Moderate accumulation (1.48- to 1.86-fold) was observed in the mean systemic total (14)C plasma concentrations at steady state (day 7) compared with single dose (day 1). The mean total (14)C eliminated was 3.5-fold and 3.7-fold greater in the urine than the feces for cohort A and cohort B, indicating that (14)C-AL-8309 is primarily excreted through renal elimination. Single and multiple topical doses of AL-8309B were found to be safe and well-tolerated in healthy subjects. This is the first reported use of accelerator mass spectrometry technology with a topically applied ophthalmic product.