Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility.

BACKGROUND

MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model.

OBJECTIVE

To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model.

DESIGN, SETTING, AND

PARTICIPANTS

Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments.

RESULTS AND LIMITATIONS: All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time.

CONCLUSIONS

Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.