Model-Based Steady State Pharmacokinetic Predictions Using High Throughput Cassette Infusion Approach in Mice

Achieving and characterizing steady-state drug concentrations is an essential objective for evaluating exposure-response relationships in preclinical pharmacology. This study assessed the pharmacokinetics (PK) of Fulvestrant, Imipramine, and Brivaracetam using cassette dosing. In vitro liver stability assays with mouse liver microsomes and hepatocytes, both individually and in combination, showed no significant drug-drug interactions. Single-dose subcutaneous (SC) PK studies in CD-1 mice provided absorption, clearance, and distribution parameters to model infusion rates targeting steady-state concentrations (C_ss). A 168-hour SC cassette infusion via Alzet osmotic pumps was used to validate predictions. Brivaracetam had the highest exposure and lowest clearance, while Imipramine showed rapid elimination. Compartmental modeling accurately predicted infusion doses, targeting C_ss of 60 ng/mL. Observed C_ss values were lower than predicted, with Imipramine showing the closest match. All compounds reached steady-state within 24-36 hours, and clearance/exposure rankings were consistent across models and experiments. This integrated approach combining SC PK profiling, modeling, and cassette infusion enabled model-informed dose prediction and qualitative validation, which can support early PK evaluation and formulation development in drug discovery.