Intravesical gemcitabine: a phase 1 and pharmacokinetic study

Area of Science:

• Urology
• Oncology
• Pharmacology

Background:

• Superficial bladder cancer treatment often involves transurethral resection and intravesical therapy.
• Current intravesical agents like Mitomycin C, Epirubicin, and BCG have limitations, necessitating exploration of new agents.
• Gemcitabine, a deoxycytidine analogue, is effective and well-tolerated systemically for various cancers, including advanced bladder cancer.

Purpose of the Study:

• To investigate the safety and pharmacokinetics of intravesical gemcitabine at three different dose levels.
• To evaluate the tolerability and systemic absorption of gemcitabine when administered directly into the bladder.

Main Methods:

• Patients with superficial bladder cancer (excluding pT1G3 or CIS) received six weekly intravesical instillations of gemcitabine (1000, 1500, or 2000 mg in 50 ml saline).
• Blood samples were collected pre-instillation and at multiple time points post-instillation (5, 30, 60, 120 minutes) for hematology and pharmacokinetic analysis.
• Dose modifications were planned based on dose-limiting toxicities, and side effects were systematically recorded.

Main Results:

• A total of 10 patients were treated across the three dose levels, with several having highly recurrent tumors prior to treatment.
• Seven patients experienced mild, reversible side effects (e.g., dysuria, headache, fatigue), all classified as WHO grade 1.
• Gemcitabine plasma levels and its metabolite difluorodeoxyuridine were immeasurable or low, indicating minimal systemic absorption and a favorable safety profile.

Conclusions:

• Intravesical gemcitabine demonstrated minimal and reversible side effects at the tested doses.
• Pharmacokinetic data strongly suggest that intravesical administration of gemcitabine is safe due to very low systemic exposure.