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

Abstract

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.

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

“…Case Example 4. A successful case example of the application of [ 14 C]-labeled microtracer dose to humans has been documented (Iyer et al, 2012). The primary objective was to characterize the PK of AL-8309B, an extensively metabolized drug, after single-and multipleday topical dosing in healthy human subjects.…”

Pharmacokinetics and absorption mechanism of tandospirone citrate

“…administration, indicating extensive metabolism of TDS in rats. According to Natsui et al (2007) and Iyer et al (2012), TDS undergoes abundant metabolic pathways in vivo, primarily mediated by CYP3A4, with 1-PP being its primary active metabolite. Due to its significant hepatic first-pass effect, its absolute bioavailability is very low.…”

“…Therefore, the aim of this study is to investigate the absolute bioavailability and absorption mechanism of TDS, providing data support for its further development and utilization. The major active metabolite of TDS is 1-[2-pyrimidyl]-piperazine (1-PP) (Iyer et al, 2012;Hu et al, 2019). Initially, we examined the absolute bioavailability of TDS in rats and comprehensively assessed the pharmacokinetic characteristics of both TDS and 1-PP.…”

Opportunities in Low-Level Radiocarbon Microtracing: Applications and New Technology

“…This study design has been discussed for years, since AMS became available, without many industry adopters. ‘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’ was the first reported use of AMS with a topically applied ophthalmic product [51]. To our knowledge, it was also the first (and perhaps only) instance where multiple radiolabeled doses were administered to steady-state conditions.…”