SUMMARY

• INLEXZO (gemcitabine intravesical system) is an intravesical drug releasing system (iDRS), referred to as TAR-200 in literature.¹ 
• Please refer to the full Prescribing Information for INLEXZO for information regarding pharmacokinetics under CLINICAL PHARMACOLOGY.²
• van Valenberg et al (2024)³ evaluated the safety, tolerability, and preliminary antitumor effect of INLEXZO in patients with recurrent intermediate-risk non-muscle-invasive bladder cancer (NMIBC) in a phase 1b study (N=12).
  • Plasma gemcitabine concentrations remained below the detection level; dFdU concentration ranged between 0.101 and 0.163 µg/mL.
  • Urine gemcitabine concentrations were detectable after 7 days of instillation; urine dFdU concentration ranged between 1.48 and 0.36 µg/mL.
• Daneshmand et al (2022)⁴ evaluated the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of INLEXZO as neoadjuvant treatment prior to radical cystectomy in a phase 1b study in patients with newly diagnosed muscle-invasive bladder cancer (MIBC) who were ineligible for or refused cisplatin-based combination chemotherapy (N=23).
  • The mean urinary concentrations of gemcitabine/dFdU were 18.5/6.7 µg/mL (day 3) and 6.6/2.3 µg/mL (day 7) in the first dosing cycle; 15.0/4.4 µg/mL (day 24) and 7.8/2.7 µg/mL (day 28) in the second dosing cycle.
  • Plasma dFdU was detected in 23 out of 110 samples at low concentrations (0.1-0.3 mg/mL); plasma gemcitabine was not found in any sample.
• Daneshmand et al (2024)⁵ presented results of Project Penelope, a preclinical study that compared the penetration, retention, and tissue distribution of gemcitabine and its active metabolites (diphosphate and triphosphate of gemcitabine) with INLEXZO versus traditional intravesical instillation methods in minipigs (N=5).
  • With INLEXZO, gemcitabine diphosphate and triphosphate concentrations were sustained in all bladder tissue layers for up to 96 hours.
  • With INLEXZO, higher gemcitabine diphosphate and triphosphate concentrations were maintained in the urothelium and lamina propria compared with muscle.
• Alternative Formats of Information
  • A video summary of Daneshmand et al (2024)⁵ can be accessed in the following link:
    • Video: Poster Summary: Project Penelope

Product labeling

• INLEXZO (gemcitabine intravesical system) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INLEXZO-pi.pdf.
• INLEXZO (gemcitabine intravesical system) [Instructions for Use]. Horsham, PA: Janssen Biotech, Inc; https://www.janssenlabels.com/package-insert/product-instructions-for-use/INLEXZO-ifu.pdf.

Section 12 Clinical Pharmacology

12.3 Pharmacokinetics

• The systemic exposure of gemcitabine and the inactive uracil metabolite (2´deoxy2´,2´difluorouridine [dFdU]), were evaluated between Days 2 and 7 during the indwelling period. The plasma gemcitabine concentrations were below the lower limit of quantification (0.1 µg/mL) in all patients at all time points. Eighteen patients (17%) had at least one quantifiable plasma dFdU concentration above the lower limit of quantification (0.1 µg/mL) and the maximum observed plasma dFdU concentration was 0.4 µg/mL. Plasma concentrations of both gemcitabine and dFdU are estimated to be less than 1% of the expected C_max after intravenous administration of gemcitabine.² 

Excretion

• Gemcitabine and dFdU are excreted in urine throughout the indwelling period for INLEXZO. Of the total gemcitabine dose, 77% was excreted by Day 7 and 99% was excreted by Day 21 in urine as gemcitabine and dFdU.² 
• Mean urinary excretion on Days 2 through 5 ranged from 21 to 32 mg per day excreted in the urine as gemcitabine and dFdU.² 

CLINICAL DATA

Phase 1 Studies

van Valenberg et al (2024)³ evaluated the safety, tolerability, and preliminary antitumor effect of INLEXZO in patients with recurrent intermediate-risk NMIBC in a prospective, open-label, phase 1b study (N=12).

Study Design/Methods

• Patients received two 7-day (arm 1) or 21-day (arm 2) dosing cycles of INLEXZO over a 4- to 6-week period; between diagnostic cystoscopy and complete transurethral resection of the bladder tumor (TURBT).
• In arm 1, patients received two 7-day INLEXZO cycles, with the first INLEXZO inserted on day 0 and removed on day 7, followed by a 14-day rest period, and the insertion of a second INLEXZO on day 21.
• In arm 2, INLEXZO was administered in two consecutive 21-day cycles, with the first insertion on day 0 and replacement on day 21.
• Subsequent TURBT or bladder biopsy was performed on days 28 and 42 for arms 1 and 2, respectively.
• A post-TURBT/final PK visit occurred on days 32 and 47 for arms 1 and 2, respectively, before patients began a 2-year surveillance period for recurrence assessment.
• Primary endpoint: Safety
• Secondary endpoints: Tolerability, PK, and preliminary efficacy (complete response and partial response rates)

Results

• A total of 12 patients were enrolled (arm 1, n=11; arm 2, n=1) to receive 1 or more doses of INLEXZO.
• All 12 patients completed post-TURBT/final PK visit and entered the 2-year surveillance period.
• Plasma gemcitabine concentrations remained below the detection level; dFdU concentration ranged between 0.101 and 0.163 µg/mL.
• Urine gemcitabine concentrations were detectable after 7 days of instillation, with the
• maximum mean concentrations observed 3 days after both dosing cycles (range, 18.2- 15.7 µg/mL); urine dFdU concentration ranged between 1.48 and 0.36 µg/Ml.

Daneshmand et al (2022)⁴ conducted an open-label phase 1b study to evaluate the safety, tolerability, preliminary efficacy, and PK of INLEXZO as neoadjuvant treatment prior to radical cystectomy in patients with newly diagnosed MIBC who were ineligible for or refused cisplatin-based combination chemotherapy (N=23).

Study Design/Methods

• Patients were serially enrolled in 2 study arms; arm 1 consisted of patients with residual tumor >3 cm after TURBT and arm 2 consisted of patients with residual tumor <3 cm after TURBT.
• Patients in both arms received two 7-day dosing cycles of INLEXZO with a 14-day resting period in between cycles, before undergoing RC on study days 28 and 42 for study arms 1 and 2, respectively.
• In arm 1, gemcitabine and dFdU levels were measured in plasma and urine on days 1, 3, 7, and 14 of each treatment cycle, and on day 14; in arm 2, they were measured in plasma only.
• Primary endpoint: Safety
• Secondary endpoints: Tolerability, PK, and preliminary efficacy (pathological complete response and pathological partial response)

Results

• A total of 23 patients were enrolled (arm 1, n=11; arm 2, n=12) and received at least 1 INLEXZO insertion.
• In the first dosing cycle, the mean urine concentrations of gemcitabine and dFdU, respectively, were 18.5 and 6.7 µg/mL on day 3 and 6.6 and 2.3 µg/mL on day 7.
• In the second dosing cycle, the mean urine concentrations of gemcitabine and dFdU, respectively, were 15.0 and 4.4 µg/mL on day 24 and 7.8 and 2.7 µg/mL on day 28.
• Plasma gemcitabine was not found in any sample at any time point.
• Plasma dFdU was detected in 23 of 110 samples at low concentrations, ranging from 0.1 to 0.3 µg/mL. Additional analyses suggested patients with MIBC (cT3 tumors) at the time of RC accounted for the majority of cases of plasma dFdU exposure.⁶

PRECLINICAL DATA

Project Penelope

Daneshmand et al (2024)⁵ compared the penetration, retention, and tissue distribution of gemcitabine and its active metabolites (diphosphate and triphosphate of gemcitabine) with INLEXZO versus traditional intravesical instillation methods in minipigs (N=5).

Study Design/Methods

• Three minipigs were treated with intravesical gemcitabine instillation, and 2 minipigs were treated with INLEXZO.
• All minipigs were assessed for penetration of active gemcitabine metabolites across different tissues of the bladder wall for over 96 hours.
• Collected samples included the dome (urothelium and lamina propria), left and right lateral wall, and trigone. Processed samples were analyzed for gemcitabine and its active metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS).
• The 3 minipigs receiving intravesical gemcitabine instillation were administered a 50 mL solution containing 2 g of freebase equivalent of gemcitabine hydrochloride (dissolved in saline at 40 mg/mL) via a Foley balloon catheter for 2 hours.
• The 2 minipigs receiving INLEXZO were administered 225 mg of freebase equivalent of gemcitabine. INLEXZO was inserted directly into the bladder, which was left in place for the duration of the study until necropsy.
• Tissue samples were collected at necropsy at different time intervals after instillation (animal 1, 2 hours; animal 6, 24 hours; animal 5, 96 hours) and INLEXZO insertion (animal 4, 48 hours; animal 3, 96 hours). See Figure: Treatment Administration Schedule for Minipigs.

Results

• With INLEXZO treatment, gemcitabine diphosphate and triphosphate levels were detectable in all bladder tissue layers during the 48- and 96-hour indwelling periods. See Figure: Mean Concentrations of Gemcitabine Active Metabolites in Bladder Tissue Layers After Treatment With INLEXZO.
• Active metabolite concentrations were higher in the urothelium and lamina propria than in muscle; the concentrations remained high for up to 96 hours in both tissue samples.
• Active metabolite concentrations were lower than those observed 2 hours after gemcitabine instillation but were sustained across all bladder tissues for up to 96 hours.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 22 August 2025.