Pharmacokinetic study to optimize the intravesical administration of gemcitabine

Abstract

Study Type – Therapy (case control) Level of Evidence 3b OBLECTIVES To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS Six arms of three patients each with a non‐muscle‐invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5–3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High‐pressure liquid chromatography/high‐resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5–3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2‐h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical 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.…”

Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial

“…For immediately pre-TURBT intravesical EMDA mitomycin, about 30 min before spinal or general anaesthesia TURBT patients received 40 mg mitomycin dissolved in 100 mL sterile water, 15,18 infused intravesically through the Foley catheter by gravity and retained in the bladder for 30 min, while 20 mA pulsed electric current for 30 min was given externally. The mitomycin solution was drained and TURBT was done, subsequently continuous intravesical irrigation with saline for 8-18 h, to prevent clot formation or retention and related complications.…”

Advances in intravesical therapy for urinary tract disorders

“…Since patients have to empty the bladder after every episode of drug instillation, a typical bladder residence time for instilled drugs is only of 2h 34, 35 . Frequent drug administration is therefore necessary to increase the duration of drug action and overcome the drug washout by voiding.…”

“…Bladder residence time of 2h is typical for instilled drugs due to the patient need to empty the bladder after instillation 34, 35 . Behavior modifications such as reduced water intake can be beneficial to intravesical drug delivery.…”