Model-based steady state pharmacokinetic predictions using high throughput cassette infusion approach in mice

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Preclinical Drug Development

Background:

• Achieving steady-state drug concentrations is crucial for preclinical exposure-response evaluations.
• Cassette dosing allows for simultaneous pharmacokinetic assessment of multiple compounds.

Purpose of the Study:

• To assess the pharmacokinetics (PK) of Fulvestrant, Imipramine, and Brivaracetam using cassette dosing.
• To model infusion rates for achieving target steady-state concentrations (C_ss) in mice.
• To validate model-informed dose predictions through cassette infusion.

Main Methods:

• In vitro liver stability assays (microsomes, hepatocytes) to assess drug-drug interactions.
• Single-dose subcutaneous (SC) PK studies in CD-1 mice.
• Compartmental modeling to predict PK parameters and infusion rates.
• 168-hour SC cassette infusion using Alzet osmotic pumps for validation.

Main Results:

• No significant in vitro drug-drug interactions were observed.
• Brivaracetam exhibited high exposure and low clearance; Imipramine showed rapid elimination.
• Compartmental modeling accurately predicted infusion doses, though observed C_ss were lower than predicted.
• All compounds reached steady-state within 24-36 hours, with consistent clearance/exposure rankings.

Conclusions:

• An integrated approach combining SC PK profiling, modeling, and cassette infusion enables effective model-informed dose prediction.
• This methodology supports early PK evaluation and formulation development in drug discovery.
• The study demonstrated the utility of cassette dosing and modeling for predicting steady-state drug concentrations.