Original article
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,☆☆

https://doi.org/10.1016/j.urolonc.2016.11.019Get rights and content

Highlights

  • MitoGel is a novel drug formulation intended for the treatment of UTUC.

  • We evaluated serial retrograde instillations of MitoGel in a swine animal model.

  • All 27 animals received their scheduled doses per protocol.

  • No clinical adverse events or meaningful laboratory changes were observed.

  • Mitomycin absorption was minimal and well below toxicity thresholds.

  • Microscopic findings were mild and lacked associated clinical adverse findings.

  • Retrograde administration of MitoGel was feasible and safe in this animal model.

Abstract

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 8 mg/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.

Introduction

Retrospective studies have demonstrated that in select cases of low-grade upper tract urothelial cancer (UTUC), renal-sparing management provides cancer-specific outcomes equivalent to radical nephroureterectomy [1], [2]. Given the known effect of radical nephroureterectomy on renal functional outcomes [3], and the known association between surgically induced chronic kidney disease and survival [4], renal-sparing management of low-grade UTUC provides superior renal functional outcomes while maintaining adequate cancer control in appropriately selected patients. However, renal-sparing management carries with it numerous technical challenges. The difficult to access and delicate nature of the upper urinary tract can prevent accurate disease evaluation, risk stratification, and endoscopic tumor ablation, often necessitating repeated interventions under general anesthesia. In addition, topical agents, who have been shown to reduce the risk of recurrence in the bladder, remain within the upper urinary tract for a very brief period of time, owing to ureteral peristalsis and the propensity of the upper tract to rapidly drain liquid agents. As such, despite the potential benefits represented by renal-sparing management, these various challenges remain obstacles to its use, and help to explain the significant number of patients who are treated with extirpative nephroureterectomy for even low-risk forms of UTUC [5], [6].

MitoGel is a novel drug, composed of a mixture of aqueous polymers with reverse-thermal gelation properties (RTGel) and mitomycin C (MMC). When cold, MitoGel is a liquid and on warming to body temperature, its viscosity increases rapidly to that of a thick gel. Initial assessment of a comparable formulation in patients with low-grade bladder cancer supports a chemoablative effect on these tumors [7]. Given these properties, there is an interest in using MitoGel as a treatment for UTUC, where it could be instilled into the upper tract as liquid, gelatinize, and then slowly dissolve with the production of urine. This dissolution process would result in a sustained release of MMC into the upper urinary tract over a few hours. Extended exposure of the urothelium to MMC was previously shown to be an important parameter in its antitumor activity in both in vitro and in vivo settings [8], [9]. Although antegrade administrations of MitoGel have been evaluated in a preclinical model [10], the safety and feasibility of retrograde administrations of MitoGel is not fully established. As such, we sought to evaluate feasibility and safety of retrograde MitoGel use in a large animal model.

Section snippets

Study design

We used adolescent female Yorkshire swine as our animal model given the noted similarities between human and swine urinary tract size, anatomy, and urodynamics [11]. Only female pigs were used owing to the fact that male pig urethral anatomy precludes cystoscopic or catheterized access to the bladder. Pigs ranged in age from 17 to 22 weeks (weight 62–80 kg). We used a total of 42 animals with a 5-group study design (Table 1). Animals were assigned to treatment group using a simple randomization

Results

No adverse clinical events attributable to retrograde treatment with MitoGel, sterile water, or RTGel alone were observed in any of the study animals. In most animals, all clinical observations were considered to be within normal limits for animals of this age and strain. Animals gained weight at approximately the same rate over the 6-week dosing and 1-month recovery period (Supplementary Table 1). Instillation of MitoGel, RTGel, or sterile water to the upper urinary tract was not associated

Discussion

Renal-sparing treatment of UTUC is associated with challenges at multiple stages of disease management. Accurate disease risk assessment is hampered by difficulties in obtaining sufficient biopsy material to accurately determine grade and stage, and both undergrading and understaging on endoscopic biopsies have been observed [14]. Treatment of the disease is not only challenged by the difficulties in achieving thorough endoscopic ablation of tumors but also by the technical task of trying to

Conclusion

Serial unilateral retrograde instillations of up to 56 mg of MitoGel into the upper tracts of the Yorkshire swine produced no observable adverse clinical effects. No evidence of renal dysfunction, myelosuppression, or sepsis was observed. Peak levels of plasma MMC were 2 orders of magnitude below the recognized toxicity threshold, and decreased to undetectable levels within 10 hours. Histologic changes within the tissues of the urinary tract were mild, resolved over time, and were of limited

Acknowledgments

The authors would like to acknowledge Dr. Keith Nelson D.V.M., Ph.D., who performed the pathologic analysis for the study.

References (18)

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    The major challenge of adjuvant endocavitary treatment resides in specific anatomic and physiologic characteristics of the upper urinary tract which has no storage capacity and is bathes continuously by the downward flow of urine produced by the kidneys [14]. To overcome these limitations, novel methods such as slow-release formulations including stents and hydrogel polymers with reverse-thermal gelation properties (liquid at cold temperature and soft, adherent gel at body temperature) and mitomycin C (MMC) have been developed and tested in preclinical models [17–19]. The aim of this review and meta-analysis was to investigate the oncologic efficacy of endocavitary therapies for the treatment of UTUC to create an up-to-date reference point for comparison to these new methods of drug delivery.

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Results herein were previously presented as a podium presentation at the American Urological Association Annual Meeting on May 7, 2016 in San Diego, CA.

☆☆

This work was supported by UroGen Pharma, Ltd. Karim Chamie is supported by the Flax Foundation.

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