Pudexacianinium (ASP5354) chloride for ureter visualization in participants undergoing laparoscopic, minimally invasive colorectal surgery

Abstract

Background Intraoperative ureteral injury, a serious complication of abdominopelvic surgeries, can be avoided through ureter visualization. Near-infrared fluorescence imaging offers real-time anatomical visualization of ureters during surgery. Pudexacianinium (ASP5354) chloride is an indocyanine green derivative under investigation for intraoperative ureter visualization during colorectal or gynecologic surgery in adult and pediatric patients. Methods In this phase 2 study (NCT04238481), adults undergoing laparoscopic colorectal surgery were randomized to receive one intravenous dose of pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg. The primary endpoint was successful intraoperative ureter visualization, defined as observation of ureter fluorescence 30 min after pudexacianinium administration and at end of surgery. Safety and pharmacokinetics were also assessed. Results Participants received pudexacianinium 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3). Most participants were female (n = 10; 83.3%); median age was 54 years (range 24–69) and median BMI was 29.3 kg/m2 (range 18.7–38.1). Successful intraoperative ureter visualization occurred in 2/3, 5/6, and 3/3 participants who received pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg, respectively. Median intensity values per surgeon assessment were 1 (mild) with the 0.3-mg dose, 2 (moderate) with the 1.0-mg dose, and 3 (strong) with the 3.0-mg dose. A correlation was observed between qualitative (surgeon’s recognition/identification of the ureter during surgery) and quantitative (video recordings of the surgeries after study completion) assessment of fluorescence intensity. Two participants experienced serious adverse events, none of which were drug-related toxicities. One adverse event (grade 1 proteinuria) was related to pudexacianinium. Plasma pudexacianinium concentrations were dose-dependent and the mean (± SD) percent excreted into urine during surgery was 22.3% ± 8.0% (0.3-mg dose), 15.6% ± 10.0% (1.0-mg dose), and 39.5% ± 12.4% (3.0-mg dose). Conclusions In this study, 1.0 and 3.0 mg pudexacianinium provided ureteral visualization for the duration of minimally invasive, laparoscopic colorectal procedures and was safe and well tolerated.

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 observed plasma and spot urine concentrations in the phase 2 study 24 were generally within the range of the model predictions, although high IIV was observed in patients during surgery compared with those in healthy participants (Figure 5). There were difficulties in spot urine PK sample collection in patients under anesthesia because their urine production rates were very low and intermittent, while urine production rates in the phase 1 study were very high because participants were allowed to consume water ad libitum throughout the study.…”

“…Therefore, by selecting 1.0 mg as the central dose, 3 dose levels of 0.3, 1.0, and 3.0 mg were proposed for the phase 2 study using a common ratio of 3 to differentiate between doses. To describe the results of this phase 2 study briefly, successful intraoperative ureter visualization occurred in 2 of 3, 5 of 6, and 3 of 3 participants who received the 0.3, 1.0, or 3.0 mg dose, respectively 24 . Pudexacianinium was safe and well tolerated, with only 1 adverse event considered related to treatment.…”

“…The phase 2 study (NCT04238481) was a randomized, open‐label, dose‐ranging clinical trial in adult participants undergoing laparoscopic, minimally invasive colorectal surgery during which the need for anatomic visualization of the ureter was anticipated 24 . A total of 12 participants were randomly assigned and received an intravenous pudexacianinium dose of 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3).…”

“…After the phase 2 study was conducted with the doses proposed based on the simulations, the clinical data were compared with those in the model. The ability of the developed PPK model to simulate plasma and spot urine concentration‐time profiles in the phase 2 study 24 was confirmed using overlay plots of observations and 90% prediction intervals using generated data for 1000 simulated patients whose urine production rate ranged from 0.2 to 2.0 mL/min (low urine production rate under anesthesia as observed in the phase 2 study) or 1.0 to 4.5 mL/min (normal or high urine production rate as observed in the phase 1 study). The generated urine production rate assuming a uniform distribution in the population was used as a constant value per patient in the simulation.…”

“…As an experimental NIR‐F dye, pudexacianinium and its analog CD‐NIR‐1 demonstrated the ability for intraoperative ureteral identification in normal rats and minipigs, and rat models of acute kidney injury, 17–19 and recently the usefulness of pudexacianinium as an agent for imaging various types of cancer was also investigated in mouse models 20–22 . Pudexacianinium is currently being developed for real‐time intraoperative ureter visualization during surgery with multiple clinical studies completed to date 23,24 …”