Randomized, Double‐Blind, Controlled Study to Evaluate Safety and Pharmacokinetics of Single Ascending Doses of ASP5354, an Investigational Imaging Product, in Healthy Adult Volunteers

Abstract

Intraoperative ureter identification helps reduce the risk of ureteral injury. Currently, no suitable agents for real-time ureter visualization are approved. ASP5354 (TK-1) is a novel indocyanine green derivative. In this first-in-human phase 1, double-blind, sequential ascending-dose study, urethral catheters were placed in 6 healthy volunteers who were randomized to single-dose, intravenous ASP5354 0.1 mg (n = 4) or placebo (n = 2). Sequential dose escalations to 0.5-, 2-, 8-, and 24-mg ASP5354 in new cohorts were contingent upon Dose-Escalation Committee approval after review of pharmacokinetic (PK) and safety data. Blood and urine samples were collected over 24 hours following dose administration. Objectives were to assess the safety/tolerability and PK of ASP5354. Treatment-emergent adverse events (TEAEs) were reported in 3 (15%) and 2 (20%) participants in the ASP5354 and placebo groups, respectively. In the former, there were 6 TEAEs (5/6 grade 1-2). One ASP5354 participant experienced grade 3 pyelonephritis, attributed to the catheter. No TEAEs were related to ASP5354. Mean plasma terminal elimination half-life ranged from 2.1 to 3.6 hours, with near complete urinary excretion of unchanged ASP5354 within 24 hours after administration. Linear and dose-proportional PK were observed. These results support further evaluation of ASP5354 at doses up to 24 mg for intraoperative near-infrared fluorescence ureter visualization.

Population Pharmacokinetic Modeling and Simulation of Pudexacianinium (ASP5354) for Dose Setting of a Phase 2 First‐in‐Patient Study: A Novel Imaging Agent for Intraoperative Ureter Visualization during Abdominopelvic Surgery

“…The lower limit of quantification was 0.001 μg/mL for plasma concentrations and 0.02 μg/mL for urine concentrations. Details of the analytical methods were reported by Murase et al 23 Computer Software Data sets were prepared using SAS for Windows v.9.4 (SAS Institute, Inc., Cary, NC, USA). The modeling, simulations, and postprocessing were conducted in Metworx v.20.12.2 (Metrum Research Group, Tariffville, CT, USA).…”

“…A phase 1, first-in-human, double-blinded, randomized, controlled, single-ascending-dose study in healthy adult participants (NCT03698305) 23 Data from the phase 1 study were used for PPK model development.…”

“…[20][21][22] Pudexacianinium is currently being developed for real-time intraoperative ureter visualization during surgery with multiple clinical studies completed to date. 23,24 Photo-optically, pudexacianinium shows NIR-F properties similar to those of ICG, with an absorption of 780 nm and a fluorescence emission of 820 nm but, due to its hydrophilicity, it is excreted rapidly and entirely into the urine after intravenous adminis-tration. Furthermore, the real-time urine pudexacianinium concentration is considered a theoretically good pharmacodynamic surrogate marker for ureter visualization.…”

In Vivo Optical Imaging of Bladder Cancer Tissues in an MB49 Bladder Cancer Orthotopic Mouse Model Using the Intravesical or Intravenous Administration of Near-Infrared Fluorescence Probe

“…In addition, CD-NIR-1 was transferred into the urine through specific and ultra-rapid renal clearance with no chemical modification, following the intravenous administration of CD-NIR-1 in rat, mouse, and macaque models. In 2021, an analog of CD-NIR-1, ASP5354 (Figure 1), formerly termed TK-1, which emits fluorescence at λ max 815 nm in human venous whole blood [15], was preclinically demonstrated to be selectively excreted via the kidneys to the bladder, and indicated no significant toxicity in a toxicological study in cynomolgus monkeys [16], and assessed the safety/tolerability and pharmacokinetics in its first-in-human phase 1 [17]. In this study, real-time imaging of bladder cancer using ASP5354 was investigated in a well-characterized mouse model in which MB49 mouse bladder cancer cells were orthotopically and syngeneically implanted in the mouse bladder [18].…”

Near-Infrared Fluorescence Imaging of Renal Cell Carcinoma with ASP5354 in a Mouse Model for Intraoperative Guidance

“…Therefore, these probes are suitable for renal imaging after intravenous administration. Recently, the safety/tolerability and pharmacokinetics of ASP5354 have been assessed in its first human phase 1 trial [28]. This study aimed to investigate the usefulness of ASP5354 as an imaging agent for NIRF differentiation between renal cell carcinoma and normal tissues in a mouse model.…”