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

Pudexacianinium (ASP5354) chloride is an indocyanine green derivative designed to enable enhanced ureter visualization during surgery. The objective of the present analysis was to determine appropriate doses of pudexacianinium for a phase 2, dose‐ranging study (NCT04238481). Real‐time urine pudexacianinium concentration is considered a good pharmacodynamic surrogate marker, since ureter visualization likely depends on its concentration in the ureter. Using plasma and urine concentrations of pudexacianinium from a phase 1 single‐ascending‐dose (0.1‐24.0 mg) study in healthy participants, a 3‐compartment population pharmacokinetic model with a urine output compartment was developed and effectively described the concentration‐time profiles. The individual estimated glomerular filtration rates had a significant impact on drug clearance. Simulations suggested that a 1.0 mg intravenous injection would achieve target urine concentrations over 1 μg/mL (determined from previous nonclinical studies) for 3 hours postdose, assuming a urine production rate of 1.0 mL/min. Based on this simulation, doses of 0.3, 1.0, and 3.0 mg were proposed for the phase 2 study. The observed plasma concentrations were generally consistent with model predictions. For urine, although only limited data could be obtained due to the difficulties of spot urine collection from surgical patients, intraoperative ureter visualization was successful at 1.0 and 3.0 mg.