(S-006) Population Pharmacokinetics and Exposure-Response Analysis for TAR-200, an Intravesical Drug Delivery System for Bladder Cancer Treatment

Shihao Hu – Janssen Research & Development; Dongfen Yuan – Janssen Research & Development; Mengjie Li – Janssen Research & Development; Hui Tian – Janssen Research & Development; Yaming Su – Janssen Research & Development; Shalaka Hampras – Janssen Research & Development; Hussein Sweiti – Janssen Research & Development; Mahesh Samtani – Janssen Research & Development

Objectives: TAR-200 is an intravesical system that provides a sustained local release of gemcitabine into bladder urine.1 Data from the pivotal Phase 2b SunRISe-1 study demonstrated that treatment with TAR-200 monotherapy achieved a high, clinically meaningful and statistically significant CR rate of 83.5%. Each TAR-200 intravesical system contains 225 mg gemcitabine and indwells in the bladder for 21 days. Upon release and active transport into cells, gemcitabine is phosphorylated intracellularly to the active metabolites, as well as converted into the inactive metabolite, 2’,2’-difluorodeoxyuridine (dFdU) by deamination. The objectives of this analysis were to: (1) develop a popPK model of TAR-200 to characterize the urine PK and variability of gemcitabine-related components (GRC, gemcitabine+dFdU); (2) explore the urine exposure-efficacy relationship for the primary efficacy endpoint, complete response (CR) rate.

Methods: The SunRISe-1 study evaluated the efficacy and safety of TAR-200 alone, cetrelimab alone, or TAR-200 in combination with cetrelimab for the treatment of patients with Bacillus Calmette-Guérin-unresponsive, high-risk non-muscle-invasive bladder cancer. In this clinical study, urine gemcitabine and dFdU were measured daily for 7 days after insertion of TAR-200 in participants who received TAR-200 alone or in combination with cetrelimab, as part of the SunRISe-1 study. A popPK model was developed to describe the urine GRC amount-time profiles using nonlinear mixed effect modeling. The release of gemcitabine from TAR-200 was modeled using a sequential zero- and first- order process. The removal of GRC in the bladder urine due to urination was described via compartment reset technique in the model. The typical release profile of TAR-200 was simulated using the typical model parameters. Subsequently, graphical analysis was performed to explore the relationship between observed and model-predicted urine exposure and CR rate in TAR-200 monotherapy cohort.

Results: The observed urine GRC PK was adequately described by the developed popPK model. Based on the simulated typical cumulative profile, 76.9% and 99.0% of gemcitabine was released by Day 7 and Day 21, respectively. This is consistent with the in vitro release profile (approximately 70% and 90% by Day 7 and Day 21). In participants who received TAR-200 monotherapy, CR and non-CR had comparable observed urine concentration and amount of gemcitabine as well as model-predicted 7-day cumulative GRC amount, indicating a flat E-R relationship.

Conclusions: The release of gemcitabine from TAR-200 was characterized using a popPK model with sequential zero- and first-order release. A flat urine exposure-efficacy relationship for CR rate supports the choice of the 225 mg dose.

Citations: [1] F Johannes P van Valenberg et al, Eur Urol Open Sci (2024)

Keywords: population pharmacokinetics, bladder cancer, intravesical therapy