Pharmacokinetics and pharmacodynamics of intravesical and intravenous TMX-101 and TMX-202 in a F344 rat model.

OBJECTIVES

To evaluate and compare the pharmacokinetic and pharmacodynamic properties of 2 investigational Toll-like receptor 7 agonists, TMX-101, and TMX-202 after intravenous and intravesical administration in a rat model. TLR-7 agonists are successfully used as topical treatment for various (pre)malignant skin lesions and are now under investigation as intravesical therapy for non-muscle-invasive bladder cancer.

METHODS

Rats received an intravesical instillation with TMX-101, TMX-202, or vehicle. Additionally 2 groups of rats received an intravenous injection with TMX-101 or TMX-202. Blood sampling was performed at different time points, including pre-exposure and postexposure to determine the plasma concentrations of study drugs for pharmacokinetic and pharmacodynamic analyses and to determine the plasma concentrations of cytokines (IL-2, IL-6, and TNF-α).

RESULTS

We observed no signs of toxicity after intravesical or intravenous administration. There was a limited dose dependent systemic uptake of TMX-101 and TMX-202 after intravesical administration. The systemic uptake of TMX-202 after intravesical instillation was 25 times lower compared to TMX-101.

CONCLUSIONS

This in vivo study confirms the safety of intravesical TMX-101 and TMX-202 administration, with TMX-202 showing lower systemic uptake. TMX-202 has a larger molecule-mass compared to TMX-101, and it may therefore have a favorable safety profile when treating patients with non-muscle-invasive bladder cancer intravesically.