Pharmacokinetic Study of Intravesical Gemcitabine in Carcinoma in situ of the Bladder Refractory to Bacillus Calmette-Guérin Therapy

Abstract

Introduction: Gemcitabine, a chemotherapeutic agent, has been shown to be active against transitional cell cancer of the bladder. The aim of the study was to determine the pharmacokinetic profile of gemcitabine, administered intravesically in patients with carcinoma in situ(CIS). Material and Methods: Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin (BCG) therapy were enrolled. Gemcitabine was given in 50 ml 0.9% NaCl by catheterization and held in the bladder for 1 h, once weekly for 6 consecutive weeks. The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum. Dose levels were: 1,000, 1,250, and 1,500 mg. Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months. Results: Grade-1 neutropenia was observed only in 1 patient. Grade-1 urinary frequency and hematuria were observed in 1 and 3 patients, respectively. No grade 2–4 toxicity or clinically relevant myelosuppression were observed. Gemcitabine was detectable in serum, but with an irrelevant pharmacological effect, in only 1 patient treated with 1,500 mg of gemcitabine. With regard to activity, after 6 instillations of this drug, 4 complete responses were observed. Conclusion: Intravesical gemcitabine is well tolerated and safe. No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed. These results warrant further investigation in phase-II trials.

Intravesical gemcitabine therapy for non‐muscle invasive bladder cancer (NMIBC): a systematic review

“…The low molecular weight and the high lipid solubility allow sufficient uptake into malignant urothelial cells for cytotoxicity in vivo . Our literature search identified eight studies investigating the pharmacokinetics of intravesical gemcitabine [31–38]. These studies (Table 5) have shown a high plasma clearance for gemcitabine, indicating that any drug distributed to the systemic circulation after intravesical administration, will be quickly eliminated, reducing the risk of systemic toxicity.…”

Gemcitabine versus bacille Calmette‐Guérin after initial bacille Calmette‐Guérin failure in non‐muscle‐invasive bladder cancer

“…Nine patients with CIS refractory to intravesical BCG were enrolled in a phase 1 study by Bassi et al 28 Gemcitabine was given once weekly for 6 consecutive weeks at different dose levels. Grade 1 neutropenia was observed in only 1 patient.…”

Cost-Effectiveness Analysis of Pembrolizumab for Bacillus Calmette-Guérin-Unresponsive Carcinoma In Situ of the Bladder

“…Each specific SIC required significant changes either in terms of price reduction (valrubicin) or lower 2-year metastasis rate (gemcitabine monotherapy and mitomycin) to become cost-effective relative to RCx. 20–25 These endpoints may prove useful for future studies examining these agents in the context of BCG-unresponsive CIS.…”