Pharmacokinetics of UGN-101, a mitomycin-containing reverse thermal gel instilled via retrograde catheter for the treatment of low-grade upper tract urothelial carcinoma

Abstract

Purpose To evaluate the pharmacokinetic properties of UGN-101, a mitomycin-containing reverse thermal gel used as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC), in a subset of patients participating in a phase 3 clinical trial. Methods Pharmacokinetic parameters (Cmax, Tmax, AUC(0–6), λz, t½, and AUCinf) were evaluated in six participants (male or female, ≥ 18 years) with biopsy-proven, low-grade UTUC who received the first of 6 once-weekly instillations of UGN-101 to the renal pelvis and calyces via retrograde ureteral catheter. Plasma samples were collected prior to instillation and 30 min, 1, 2, 3, 4, 5, and 6 h post-instillation. Safety was assessed by laboratory evaluations, physical exam, and adverse event monitoring. Results The mean age of the six participants was 69 years; most were male (5/6) and Caucasian (5/6). Mean (SD) Cmax was 6.24 (4.11) ng/mL and mean Tmax was 1.79 (1.89) hours after instillation. Mean apparent t½ following instillation was 1.27 (0.63) hours. Mean total systemic exposure to mitomycin up to 6 h post-instillation was 20.30 (19.69) ng h/mL. At 6 h post-instillation, mitomycin plasma concentrations of 5/6 participants were < 2 ng/mL. There were no clinically important adverse events or changes in laboratory values in any participant after a single instillation of UGN-101. Conclusion The reverse thermal gel formulation of UGN-101 is associated with higher concentration and extended dwell time of mitomycin in contact with the urothelium of the upper urinary tract while limiting systemic absorption of mitomycin. Registration NCT02793128; registered June 8, 2016.

Smart Hydrogels for Advanced Drug Delivery Systems

“…They are likely to have an exciting future, while some challenges are facing this field. Up to now, various smart hydrogels have been developed and introduced, but the commercialization of smart hydrogels as drug delivery systems is not convincing; only a few cases have entered into clinical use, including Jelmyto ® (UGN-101) as a TRH that was lunched by UroGen Pharma and received Food and Drug Administration (FDA) approval in April 2020 [ 105 ]. Indeed, given the recent advances in the pharmaceutical industry, there are still no clear legal regulations and standards for the use of smart drug-loaded hydrogels in therapeutic activities.…”

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021

“…JELMYTO is the new formulation of the cytostatic agent, i.e., mitomycin, in reverse thermal gel (RTGel TM ) (4 mg mitomycin per mL gel) that received FDA approval for treatment of low-grade upper tract urothelial cancer (UTUC). The drug is administered into the renal pelvis and calyces via a ureteral catheter tube [ 239 ]. Mitomycin (also known as mitomycin-C ) is an antibiotic isolated from Streptomyces caespitosus that was originally approved by the FDA on 29 November 1995 [ 240 ].…”

“…Reverse-thermal hydrogel formulation provides a sustained exposure that allows for increased drug concentration and dwelling time at the site of tumor compared with aqueous solutions. It also optimizes drug delivery and controls its release, leading to a reduction in off-target effects [ 239 ].…”

Antegrade Instillation of UGN-101 (Mitomycin for Pyelocalyceal Solution) for Low-Grade Upper Tract Urothelial Carcinoma: Initial Clinical Experience

“…The eventual semisolid gel allows for chemoablative therapy to remain in the collecting system for 4e6 hours without immediately being diluted or washed away by urine flow. 11 The OLYMPUS trial (a phase 3 registrational study, NCT02793128) details retrograde administration of UGN-101. 8 Here, we report our methods and early outcomes from a series of patients treated with UGN-101 via nephrostomy tube.…”

“…The eventual semisolid gel allows for chemoablative therapy to remain in the collecting system for 4–6 hours without immediately being diluted or washed away by urine flow. 11…”