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

Ahmad Shabsigh, Nir Kleinmann, Angela B Smith, Douglas Scherr, Elyse Seltzer, Mark Schoenberg, Seth P Lerner, Ahmad Shabsigh, Nir Kleinmann, Angela B Smith, Douglas Scherr, Elyse Seltzer, Mark Schoenberg, Seth P Lerner

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.

Keywords: Mitomycin; Pharmacokinetics; UGN-101; UTUC; Upper tract urothelial carcinoma.

Conflict of interest statement

AS and NK have been investigators and consultants for UroGen Pharma. ABS has been a consultant for UroGen Pharma, Merck, and Photocure, and an investigator for PCORI. SPL has received grant support for clinical trials from UroGen Pharma, Endo, FKD, JBL (SWOG), Roche/Genentech (SWOG), Vaxiion, and Viventia; has been a consultant for UroGen Pharma, Ferring, GLG, Merck, Pfizer, Roche/Genentech, QED, and Verity; has received honoraria from UroToday and Grand Rounds in Urology; is a patent holder for TCGA classifier; and has received compensation in his role as co-editor in chief for Bladder Cancer and as co-editor for the bladder cancer section of UpToDate®. ES and MS are employees of UroGen Pharma. DS declares no competing interests.

Figures

Fig. 1
Fig. 1
Mitomycin concentration vs time curve following instillation of UGN-101. LOQ, limit of quantification

References

    1. Browne BM, Stensland KD, Moynihan MJ, Canes D. An analysis of staging and treatment trends for upper tract urothelial carcinoma in the national cancer database. Clin Genitourin Cancer. 2018;16(4):e743–e750. doi: 10.1016/j.clgc.2018.01.015.
    1. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, Cowan NC, Gontero P, Van Rhijn BWG, Mostafid AH, Palou J, Shariat SF. European Association of Urology guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol. 2018;73(1):111–122. doi: 10.1016/j.eururo.2017.07.036.
    1. Hasan MN, Roupret M, Keeley F, Cracco C, Jones R, Straub M, Traxer O, Osther PJS, Brehmer M. Consultation on UTUC, Stockholm 2018 aspects of risk stratification: long-term results and follow-up. World J Urol. 2019;37(11):2289–2296. doi: 10.1007/s00345-019-02739-1.
    1. Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110(5):614–628. doi: 10.1111/j.1464-410X.2012.11068.x.
    1. Foerster B, D'Andrea D, Abufaraj M, Broenimann S, Karakiewicz PI, Roupret M, Gontero P, Lerner SP, Shariat SF, Soria F. Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature. Urol Oncol. 2019;37(7):430–436. doi: 10.1016/j.urolonc.2019.02.004.
    1. Kohut R, Zhu H. Treatment of low stage urothelial carcinoma of the ureter: trends in utilization of endoscopic management. J Urol. 2012;187(4S):e256.
    1. Upfill-Brown A, Lenis AT, Faiena I, Salmasi AH, Johnson DC, Pooli A, Drakaki A, Gollapudi K, Blumberg J, Pantuck AJ, Chamie K. Treatment utilization and overall survival in patients receiving radical nephroureterectomy versus endoscopic management for upper tract urothelial carcinoma: evaluation of updated treatment guidelines. World J Urol. 2019;37(6):1157–1164. doi: 10.1007/s00345-018-2506-1.
    1. Kleinmann N, Matin SF, Pierorazio PM, Gore JL, Shabsigh A, Hu B, Chamie K, Godoy G, Hubosky S, Rivera M, O'Donnell M, Quek M, Raman JD, Knoedler JJ, Scherr D, Stern J, Weight C, Weizer A, Woods M, Kaimakliotis H, Smith AB, Linehan J, Coleman J, Humphreys MR, Pak R, Lifshitz D, Verni M, Adibi M, Amin MB, Seltzer E, Klein I, Konorty M, Strauss-Ayali D, Hakim G, Schoenberg M, Lerner SP. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol. 2020;21(6):776–785. doi: 10.1016/S1470-2045(20)30147-9.
    1. Donin NM, Duarte S, Lenis AT, Caliliw R, Torres C, Smithson A, Strauss-Ayali D, Agmon-Gerstein Y, Malchi N, Said J, Raman SS, Holden S, Pantuck A, Belldegrun AS, Chamie K. Sustained-release formulation of mitomycin C to the upper urinary tract using a thermosensitive polymer: a preclinical study. Urology. 2017;99:270–277. doi: 10.1016/j.urology.2016.09.039.
    1. Donin NM, Strauss-Ayali D, Agmon-Gerstein Y, Malchi N, Lenis AT, Holden S, Pantuck AJ, Belldegrun AS, Chamie K. 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. Urol Oncol. 2017;35(5):272–278. doi: 10.1016/j.urolonc.2016.11.019.
    1. Meiron M, Chamie K, Lerner SP, Jeshurun M, Hakim G, Schoenberg MP, Pantuck AJ, Belldegrun AS. Mitogel: optimizing drug delivery to the upper urinary tract—a preclinical evaluation. J Urol. 2014;191(4S, Suppl):e914. doi: 10.1016/j.juro.2014.02.2471.
    1. Kleinmann N, Wirth G, Lin JS, Matin SF, Nativ O, Mayer G, Witjes JA, Shvero A, Chamie K, Pantuck AJ, Smith A, Schoenberg M, Malchi N, Hakim G, Agmon-Gerstein Y, Jeshurun-Gutshtat M, Klein I, Kopelen H, Lerner SP. Thermo reversible hydrogel based delivery of mitomycin C (UGN-101) for treatment of upper tract urothelial carcinoma (UTUC) Bladder Cancer. 2019;5(1):21–29. doi: 10.3233/BLC-180182.
    1. Accord Healthcare Inc. Mitomycin injection, powder, lyophilized, for solution. USPI 08/2-17.
    1. Crooke ST, Henderson M, Samson M, Baker LH. Phase I study of oral mitomycin C. Cancer Treat Rep. 1976;60(11):1633–1636.
    1. Barlogie B, Drewinko B. Lethal and cytokinetic effects of mitomycin C on cultured human colon cancer cells. Cancer Res. 1980;40(6):1973–1980.
    1. De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer. 1992;51(3):359–364. doi: 10.1002/ijc.2910510305.
    1. Nozue M, Todoroki T, Fukao K. 5-fu dose-dependency in mtx/s-fu sequential therapy assessed by in-vitro assay using gastric-cancer cell-lines. Oncol Rep. 1995;2(5):737–740. doi: 10.3892/or.2.5.737.
    1. Ozawa S, Sugiyama Y, Mitsuhashi Y, Kobayashi T, Inaba M. Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration–time product. Cancer Chemother Pharmacol. 1988;21(3):185–190. doi: 10.1007/BF00262767.
    1. Perry RR, Greaves BR, Rasberry U, Barranco SC. Effect of treatment duration and glutathione depletion on mitomycin C cytotoxicity in vitro. Cancer Res. 1992;52(17):4608–4612.
    1. Sadeghi HM, Seitz B, Hayashi S, LaBree L, McDonnell PJ. In vitro effects of mitomycin-C on human keratocytes. J Refract Surg. 1998;14(5):534–540. doi: 10.3928/1081-597X-19980901-11.
    1. Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res. 1991;51(15):3849–3856.
    1. Slee PH, de Bruijn EA, Leeflang P, Kuppen PJ, van den Berg L, van Oosterom AT. Variations in exposure to mitomycin C in an in vitro colony-forming assay. Br J Cancer. 1986;54(6):951–955. doi: 10.1038/bjc.1986.266.
    1. Walker MC, Masters JR, Parris CN, Hepburn PJ, English PJ. Intravesical chemotherapy: in vitro studies on the relationship between dose and cytotoxicity. Urol Res. 1986;14(3):137–140. doi: 10.1007/BF00255832.
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. doi: 10.3322/caac.21442.

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